Scientific Report - Ospedale San Raffaele

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Scientific Report - Ospedale San Raffaele
Scientific Report
2013
Scientific Report
2013
Cover image by Massimo Degano
(see Biocrystallography Unit, page 151, figure 22):
Active site of the IAGNH enzyme from T. brucei bound to a nanomolar inhibitor.
Knowledge of the active site cavity features (green transparent surface)
allows the modification of the compound (yellow sticks) to enhance its activity.
Some of the images in this book has been published in scientific papers:
Figure 2, p. 16: Modified from: Leukemia: 2013; 27(11): 21962199 doi: 10.1038/leu.2013.98
Figure 6, p. 50: Modified from: J. Clin. Invest. [published online
ahead of print June 17, 2014] doi:10.1172/JCI74664
Figure 8, p. 55: Modified from: Neurobiol. Aging: 2013; 34(11):
e13-e18 doi: 10.1016/j.neurobiolaging.2013.05.020
Figure 9, p. 57: Neuropsychopharmacology: 2013; 38(2): 313327. doi: 10.1038/npp.2012.17
Figure 15, p. 88: J. Transl. Med. 2013 Dec 13;11:310 doi:
10.1186/1479-5876-11-310
Figure 20, p. 125: J. Allergy Clin. Immunol.: 2014; 133(3):
799-806.e10 doi: 10.1016/j.jaci.2013.12.1043
Figure 34, p. 199: Cover image in: Tissue Engineering - Part A:
2014; 20(5-6)
Figure 36, p. 216: FEBS J.: 2014; 281(1): 216-231 doi:
10.1111/febs.12588
Figure 37, p. 217: Curr. Biol.: 2014; 24(4): 393-403 doi:
10.1016/j.cub.2014.01.007
Figure 40A, p. 230: Modified from: Mol. Cell. Biol.: 2013;
33(18): 3644-3658 doi: 10.1128/MCB.00302-13
Figure 43, p. 251: Neurology: 2013; 81(2): 134-143 doi:
10.1212/WNL.0b013e31829a33f8
Figure 46, p. 263: Proteomics: 2013; 94: 401-412 doi:
10.1016/j.jprot.2013.10.007
Edited by the San Raffaele Library
Layout project by Rolando Cassinari
Cover design by the San Raffaele Marketing, Fundraising & Communication Office
Printed by Grafiche Parole Nuove, Brugherio
INDEX
III
INDEX
INTRODUCTION
IX
Scientific Directors' Introduction
XII
A short visual history of the Institute
XX
San Raffaele Scientific Retreat 2013
XXI
2013 Seminars and lectures
XXIV
DIVISION OF MOLECULAR
ONCOLOGY
5
Introduction by the Directors
Research Units
11
Lymphoid malignancies Unit
Biology of multiple myeloma
Cell activation and signalling
Tumour microenvironment
Immuno-biotherapy of melanoma and solid
tumors Unit
Cancer gene therapy
B-cell neoplasia Unit
Functional genomics of cancer Unit
Lymphoid organ development Unit
Molecular histology and cell growth Unit
Preclinical models of cancer Unit
Tumor biology and vascular targeting Unit
12
12
13
13
14
15
15
16
17
18
18
19
Clinical Research Units
Digestive and pancreatico-biliary
endoscopy Unit
20
Endosonography: diagnostic and
therapeutic endoscopic ultrasound
20
Gastrointestinal surgical oncology Unit
21
Head and neck oncology Unit
21
Multidisciplinary group for thoracic surgical
oncology
22
Oncogenesis in liver neoplasms Unit
23
Pancreatic cancer Unit: biology and new
therapeutic approaches
23
Pathology Unit
24
Clinical lymphoid malignancies
24
Gynecologic oncology
25
Medical oncology Unit - Clinical trials
26
Medical oncology Unit - Phase I and lung cancer
clinical trials
26
Onco-hematology
27
Urological Research Institute (URI)
Introduction by the Director
Research Units
28
28
Urological pre-clinical research Unit
Functional urology
29
29
Clinical Research Units
Prostate cancer
Bladder cancer Unit
30
30
Renal cancer Unit
Sexual medicine Unit
31
31
Selected publications
Selected publications, URI
32
33
DIVISION OF
NEUROSCIENCE
37
Introduction by the Directors
Research Units
44
Neuropsychopharmacology Unit
Rett syndrome research group
Cell adhesion Unit
Cellular neurophysiology Unit
Developmental neurogenetics Unit
Neurobiology of learning Unit
Proteomics of iron metabolism Unit
Stem cells and neurogenesis Unit
Molecular genetics of mental retardation Unit
45
46
46
47
48
49
49
50
51
Clinical Research Units
Acute brain protection, Acute post-operative
pain, Drugs and central nervous
system Unit
Cognitive neuroscience Unit
Experimental neurosurgery Unit
Eye repair Unit
Functional neuroradiology Unit
In vivo Human molecular and structural
neuroimaging Unit
Neuroothology Unit
Psychiatry and clinical psychobiology
Sleep medicine
Clinical psychology
Motor function rehabilitation
55
56
56
57
58
59
Institute of Experimental
Neurology (INSPE)
Introduction by the Director
Research Units
60
60
61
Experimental neuropathology
Experimental neurophysiology
Molecular genetics of behaviour
Neuromuscular repair
Neuroimmunology Unit
Clinical neuroimmunology
Immunobiology of neurological disorders
Neuroimaging research Unit
Neuroimaging of CNS white matter
Human inherited neuropathies Unit
Axo-glia interactions Unit
61
61
62
62
63
64
65
66
66
67
68
52
52
52
53
54
Clinical Research Units
Inflammatory CNS disorders Unit
69
V
INDEX
Cerebrovascular disorders
Memory disorders
Movement disorders
Neuromuscular disorders
Paroxysmal events
69
70
70
71
71
Selected publications
Selected publications, INSPE
72
73
DIVISION OF METABOLIC
AND CARDIOVASCULAR
SCIENCES
81
Introduction by the Directors
Research Units
85
Coagulation and platelet biology Unit
Cardiodiabetes & core Lab
Complications of diabetes
Metabolism, nutrigenomics and cell
differentiation
Bone metabolism Unit
Coagulation service & thrombosis
research Unit
Pediatric endocrinology research
86
87
87
88
89
89
90
Clinical Research Units
Diabetes and endocrinology Unit
91
Cardio-metabolism and clinical trials
91
Fetal-maternal medicine
92
Clinical pediatric endocrinology
92
Diabetes and metabolic diseases
in children and adolescents
93
Neonatology
93
Structural heart disease Unit
94
Cardiopulmonary clinical physiology Unit
95
Cardiovascular interventions Unit
95
Center for arrhythmia research
96
Echocardiography Unit
96
Ischaemic heart disease, heart failure and
echocardiography Unit
97
Organ protection in critically ill patients,
Advanced cardiac failure and mechanical
supports Unit
98
Strategic research on heart failure Unit
99
Study and treatment of aortic disease Unit
99
Vision first Unit
100
Selected publications
101
DIVISION OF REGENERATIVE
MEDICINE, STEM CELLS
AND GENE THERAPY
107
IIntroduction by the Directors
Research Units
112
Angiogenesis and tumor targeting Unit
113
Functional genetics of muscle regeneration
Neural stem cell biology
Autoimmunity & vascular inflammation Unit
Innate immunity and tissue remodelling
Experimental hematology Unit
Gene expression and muscular dystrophy
Unit
Leukemia immunotherapy Unit
Molecular and functional immunogenetics
Unit
113
114
114
115
116
117
118
118
Clinical Research Units
Hematology and hematopoietic stem cell
transplantation Unit
Immunohematology and transfusion
medicine Unit
The San Raffaele-Telethon Institute
for Gene Therapy (HSR-TIGET)
Introduction by the Director
Research Units
Gene transfer technologies and new gene
therapy strategies Unit
Gene/Neural stem cell therapy for
lysosomal storage diseases
Gene therapy for WASP/Omenn Unit
Gene transfer into stem cells Unit
Hematopoietic stem cell based gene
therapy for the treatment of lysosomal
storage disorders Unit
Immunological tolerance Unit
Genetic autoimmune diseases
Pathogenesis and therapy of ADA-SCID Unit
Safety of gene therapy and insertional
mutagenesis Unit
Tolerogenic dendritic cells Unit
119
119
120
120
121
121
122
122
123
123
124
125
126
126
Clinical Research Units
PCRU - Gene therapy for Wiskott-Aldrich
Syndrome
127
PCRU - ADA gene transfer into hematopoietic
stem cells for the treatment of ADA-SCID 127
PCRU - Clinical trial of gene therapy in
metachromatic leukodystrophy
128
Selected publications
Selected publications, HSR-TIGET
129
130
DIVISION OF IMMUNOLOGY,
TRANSPLANTATION, AND
INFECTIOUS DISEASES
139
Introduction by the Directors
Research Units
146
Immunopathology Unit
Cellular and molecular allergology
Human virology
147
147
148
INDEX
Protein engineering and therapeutics
γδ T cells in innate and adaptive immunity
Immunobiology of HIV
AIDS immunopathogenesis Unit
Biocrystallography Unit
Cellular immunology Unit
Dynamics of immune responses Unit
Emerging bacterial pathogens Unit
Experimental immunology Unit
Infection and cystic fibrosis Unit
Leukocyte biology Unit
Lymphocyte activation Unit
Tumor immunology Unit
Viral evolution and transmission Unit
Viral pathogens and biosafety Unit
148
149
150
150
151
152
152
153
154
154
155
156
156
157
158
Protein transport and secretion Unit
Age related diseases
Molecular immunology
Chromatin dynamics Unit
In vivo Chromatin and transcription
Molecular dynamics of the nucleus
Biology of myelin Unit
Biomolecular mass spectrometry Unit
European Institute for Research in Cystic
Fibrosis (IERFC)
Genetics of common disorders Unit
Intracellular signaling pathways Unit
Molecular basis of polycystic kidney
disease Unit
NeuroGlia Unit
Regulation of iron metabolism Unit
Molecular genetics of renal disorders Unit
159
159
Clinical Research Units
Clinical Research Units
Management and antiretroviral treatment
of HIV infection
Neurovirology
Study and treatment of hepatotropic
viruses related diseases
Vaccine and immunotherapy
Clinical immunopathology and advanced
medical therapeutics Unit
Clinical transplant Unit
Pancreatic tumors Unit: immunotherapy
and β cell function substitution
Gynecological cancers immunology
Immunology in liver neoplasms
Obesity and bariatric surgery
Clinical hepato-gastroenterology
Digestive pathophysiology
187
188
188
189
190
191
191
192
192
193
193
194
194
196
196
160
161
Dento-facial histopathology Unit
Genomics of renal diseases and
hypertension Unit
Reproductive sciences Lab
Tissue engineering and biomaterials
197
198
199
161
162
Selected publications
201
162
163
163
164
164
165
CENTER FOR
TRANSLATIONAL GENOMICS
AND BIOINFORMATICS 211
Diabetes Research Institute (DRI)
Introduction by the Directors
Research Units
166
166
Experimental diabetes
β cell biology Unit
Immune-mediated diseases Unit: from
pathogenesis to treatment
167
167
168
Clinical Research Units
197
Introduction by the Directors
Research Units
213
Neurogenomics Unit
Genome function Unit
Biomolecular NMR Laboratory
Genomic Unit for the diagnosis of human
pathologies
Organelle biogenesis and motility Unit
Proteome biochemistry Unit
214
215
215
Selected publications
219
216
217
218
Prevention in Type 1 diabetes Unit
Epidemiology & data management
Islet transplantation
Childhood diabetes
169
169
169
170
EXPERIMENTAL IMAGING
CENTER
225
Selected publications
Selected publications, DRI
171
172
Introduction by the Directors
Research Units
DIVISION OF GENETICS
AND CELL BIOLOGY
Introduction by the Directors
Research Units
183
186
Advanced fluorescence microscopy and
nanoscopy research Unit
Dynamic fluorescence spectroscopy in
biomedicine
Mouse functional genetics Unit
228
229
230
231
Clinical Research Units
VII
INDEX
Clinical and experimental radiology Unit
High technology in radiation therapy Unit
Medical physics Unit
Molecular imaging Unit
Neuroradiology research group
232
232
233
233
234
Service Units
235
236
237
238
Selected publications
239
243
Brain Regeneration usIng medical Devices,
Gene vectors and stEm cells (BRIDGE)
Program in Immunology and
Bio-immunotherapy of Cancer (PIBIC)
Islet Trasplantation Program (ITP)
Human Brain Invivo Mapping with
neuroimaging (BRAINMAP)
Bone Physiopathology Program
(BoNetwork)
Correlates of HIV-Associated Immune
Response Modulation program (CHARM)
Microenvironment and Genes in Cancers
of the Blood (MAGIC)
FACILITIES
Selected publications
276
279
280
282
284
Selected publications
286
Maternal and child health Department
287
Selected publications
289
Department of internal and specialistic
medicine
291
Selected publications
292
Department of clinical neuroscience
294
Selected publications
297
Department of neurology
Selected publications
243
Department of onco-haematology
245
247
Department of medical oncology
249
Department of radiology
252
Department of urology
Selected publications
Selected publications
Selected publications
Selected publications
299
300
301
302
304
305
307
309
310
312
254
256
259
CFCM, San Raffaele-Telethon Core Facility for
Conditional Mutagenesis
260
FRACTAL, Flow cytometry Resource,
Advanced Cytometry Technical
Applications Laboratory
261
CERMAC, Centre of Excellence of High
Field Magnetic Resonance
262
ProMiFa, Protein Microsequencing Facility 262
Mouse histopathology
263
THE ETHICS COMMITTEE 266
THE CLINICAL
DEPARTMENTS
Selected publications
Head and neck Department
Department of infectious diseases
ALEMBIC, Advanced Light and Electron
Microscopy BioImaging Center
Intravital microscopy
Preclinical MRI and US facility
Pre-clinical PET facility
RESEARCH
PROGRAMMES
Department of general and specialistic
surgery
CLINICAL SERVICES
313
Pathology
Nuclear medicine
Radiotherapy
Laboratory medicine
Immunohematology and transfusion
medicine service
Emergency medicine
General intensive care
General anaesthesia and neurointensive
care Unit
315
316
316
317
Selected publications
320
317
318
318
319
WHO Collaborating Centre for Integrated
Laboratory Strengthening on Tuberculosis,
WHO Supranational Reference Laboratory
and ESCMID collaborative Centre
324
269
Cardio-thoracic-vascular Department
271
PUBLICATIONS
325
Selected publications
274
List of 2013 publications
327
INTRODUCTION
IX
SAN RAFFAELE SCIENTIFIC INSTITUTE
Scientific Director:
Francesco Montorsi*, since September 2013
Deputy Scientific Director:
Luca G. Guidotti, since September 2013
Scientific Director:
Maria Grazia Roncarolo*, until September 2013
* Professor at: Università Vita-Salute San Raffaele
XI
INTRODUCTION
Scientific Directors’ Introduction
The San Raffaele Scientific Institute (SRSI) gathers basic, translational and clinical research activities conducted within Ospedale San Raffaele (OSR) and Fondazione Centro San Raffaele (FCSR). OSR is a forprofit organization that is governed by Prof. Gabriele Pelissero (President) and Dr. Nicola Bedin (CEO);
FCSR is a non-profit entity headed by Prof. Giuseppe Banfi (General Director).
2013 was a year of high scientific productivity for SRSI. Indeed, SRSI scientific productivity continued its
upward trend as per i) quantity and quality of publications, ii) total impact factor and iii) number of clinical
trials. All of this reflects the dedication and the excellence of our scientists and clinical investigators, who
continue to be highly recognized at the national and international level.
2013 was also a year in which the SRSI governance was re-organized: on September 15th, Prof.
Francesco Montorsi was appointed as the new Scientific Director (in place of Prof. Maria Grazia Roncarolo) and Prof. Luca G. Guidotti was appointed as Deputy Scientific Director.
Research Divisions and Centers
During 2013, SRSI has maintained its previous research organization.
Six Research Divisions and two Research Centers provide critical mass and synergy in existing areas of
excellence.
RESEARCH DIVISIONS
Director
Associate Director
Molecular Oncology
Federico Caligaris-Cappio Giorgio Parmiani
Neuroscience
Gianvito Martino
Flavia Valtorta
Regenerative Medicine, Stem Cells
Luigi Naldini
Fabio Ciceri
Immunology, Transplantation
Ruggero Pardi/
Adriano Lazzarin
and Infectious Diseases
Luca G. Guidotti
Genetics and Cell Biology
Roberto Sitia
Metabolic and Cardiovascular Sciences
Ottavio Alfieri and Emanuele Bosi (Co-directors);
and Gene Therapy
Marco E. Bianchi
Zaverio Ruggeri (Coordinator for Basic Research)
RESEARCH CENTERS
Director
Co-Director
Experimental Imaging
Carlo Tacchetti
Alessandro Del Maschio
Translational Genomics and Bioinformatics
Giorgio Casari
Elia Stupka
Research Institutes
Four internal Research Institutes continue to focus on specific and coherent research themes
RESEARCH INSTITUTE
Director
San Raffaele Telethon Institute for Gene Therapy (TIGET)
Luigi Naldini
Institute for Experimental Neurology (INSPE)
Giancarlo Comi
Diabetes Research Institute (DRI)
Emanuele Bosi
Urological Research Institute (URI)
Francesco Montorsi (ad interim)
INTRODUCTION
• The “San Raffaele Telethon Institute for Gene Therapy” (TIGET), a joint venture with the Telethon Foundation, is an internationally renowned center pioneering cell and gene therapy in genetic diseases.
• The Institute for Experimental Neurology (INSPE), based on an agreement with Merck-Serono, constitutes one of the major European Institutes primarily dedicated to translational research in neuroscience.
• The Diabetes Research Institute (DRI) is part of the International DRI Federation (an organization that includes 12 other DRIs around the world) and mainly promotes basic and clinical research on Type 1 Diabetes (T1D).
• The Urological Research Institute (URI) is an internationally recognized center carrying out basic and clinical research in oncological and non-oncological diseases of the genito-urinary tract.
Research Programs
Research Programs represent strategic projects focused on specific scientific goals. During 2013, seven
Research Programs have remained active at SRSI, and they relate to dedicated areas in the fields of
Neuroscience, Oncology, Immunology, Metabolic or Infectious Diseases.
Research Programs
Head
Brain Regeneration usIng medical Devises, Gene vectors
Head:
and stEm cells (BRIDGE)
Gianvito Martino (ad interim)
Deputy Head:
Luigi Naldini (ad interim)
Program in Immunology and Bio-immunotherapy of Cancer (PIBIC)
Co-Heads:
Paolo Dellabona
Giorgio Parmiani
Pancreatic Islet Trasplantation
Co-Heads:
Lorenzo Piemonti
Paola Maffi
Human Brain In vivo Mapping with neuroimaging (BRAINMAP)
Head:
Massimo Filippi
Deputy Head:
Andrea Falini
Bone Physiopathology Program (BoNetwork)
Co-Heads:
Roberto Sitia
Enrico Gherlone
Correlates of HIV-Associated Immune Response Modulation (CHARM) Co-Heads:
Paola Cinque
Guido Poli
Microenvironment and Genes in Cancers of the Blood (MAGIC)
Co-Heads:
Paolo Ghia
Giovanni Tonon
XIII
INTRODUCTION
Scientific Directors’ Introduction
Institutional Facilities
Traditionally, strategic investments in facilities and technological platforms have been a top priority at SRSI.
As such, SRSI continue to offer state-of-the art services covering different research areas. Eight Institutional Facilities are operational at SRSI, including proteomics, flow cytometry, conditional mutagenesis,
mouse histopathology, high field magnetic resonance, light and electron microscopy and statistics.
Facility
Scientific
Manager
Supervisor
Promifa
Angela Bachi/
Annapaola Andolfo
Facility Manager
Marco E. Bianchi
Fractal
Alessio Palini
Chiara Villa
Head of Facility
Experimental models
Luca G. Guidotti
Enzo Oriani
Facility Manager
Cfcm
Marco E. Bianchi
Lorenza Ronfani
Facility Manager
Mhp
Claudio Doglioni
Francesca Sanvito
Facility Manager
Alembic
Fabio Grohovaz
Fabio Grohovaz
Head of Facility
Cermac
Enrico Smeraldi
Andrea Falini
Head of Facility
Cussb
Clelia Di Serio
Clelia Di Serio
Head of Facility
of diseases
Human resources at SRSI
As of December 2013 over 1,640 individuals - distributed throughout the 6 Research Divisions, the 2 Research Centers and the 8 Institutional Facilities - have been working at SRSI:
• 964 people, including scientists, technicians, postdoctoral fellows, PhD students and undergraduate
students, have been working on preclinical and translational research;
• 665 people, including physicians, research nurses, residents and clinical fellows have been working on
clinical research projects;
• 25 people, including heads of facility, lab managers, research associates and technicians have been
working in Institutional Facilities.
Highlights of scientific activities in 2013
News from Basic Research
• A study published in Science reports encouraging results using lentivirus gene therapy to treat the fatal
genetic disorder Metachromatic Leukodystrophy (MLD) that lacks any effective treatments. Hematopoietic stem cells were collected from children with the most severe variant of MLD, exposed to a lentiviral vector expressing the corrective gene and re-injected in the patients after a short course of
chemotherapy. Almost two years after treatment, sustained engraftment of gene corrected stem cells
and prevention of neurological disease manifestation or progression were observed (Biffi et al., Science 2013; 341, 1233158).
• A parallel study published in Science reports promising results of gene therapy in Wiskott-Aldrich syndrome (WAS), a genetic disorder characterized by thrombocytopenia and immune deficiency. Three patients received infusion of autologous hematopoietic stem/progenitor cell, transduced with a lentiviral
vector encoding WAS, following reduced chemotherapy conditioning. Molecular studies showed high
level engraftment of gene corrected stem cells (25-50%) with multilineage hematopoiesis and a safe profile of vector integration. Gene therapy resulted in improved platelet counts with decreased bleeding,
INTRODUCTION
improved immune functions and reduced infections (Aiuti et al., Science 2013; 34, 1233151).
• A study published in Nature Immunology disclosed an essential function of autophagy in the immune
system. Autophagy ensures sustainable antibody production through selective digestion of the plasma
cell secretory compartment. Moreover, autophagy is required for the maintenance of memory plasma
cells in bone marrow. This study furthers our understanding of immunity and offers a framework for
identifying new targets against multiple myeloma, the cancer of plasma cells (Pengo et al., Nat Immunol. 2013; 14:298-305).
• A study published in Nature Medicine demonstrated that a common variant in the promoter of the
UMOD gene encoding uromodulin, the most abundant protein in urine, triggers a cascade of events
that end up in hypertension and signs of chronic kidney disease. This study expands our knowledge
on the complex mechanisms that determine hypertension and chronic kidney disease and it shows
how genetic information could be exploited for personalized medicine (Trudu et al., Nat Med. 2013;
19:1655-1660).
• A study published in Nature Medicine described a new set of surface markers (CD49b and lymphocyte activation gene 3) enabling the identification and isolation of a particularly important subset of
human and mouse CD4+ T regulatory cells (Tr1 cells). The discovery makes it feasible to track Tr1 cells
in vivo and to purify Tr1 cells for cell therapy approaches aimed at inducing or restoring tolerance in subjects with immune-mediated diseases (Gagliani et al., Nat Med. 2013; 19:739-746).
• A study published in Nature Medicine shed new light in the pathogenesis of Autosomal Dominant Polycystic Kidney Disease (ADPKD), a common genetic disorder characterized by bilateral renal cyst formation. This work showed that the epithelia lining the cysts have an aberrant glucose metabolism,
characterized by anaerobic glycolysis. Glucose deprivation impairs their growth and survival. A glucose
analogue, 2-Deoxy-D-Glucose, administered to murine models of PKD effectively retarded disease
progression, providing a proof-of-concept for the use of this molecule as a safe therapeutical approach
(Rowe et al., Nat Med. 2013; 19:488-493).
• A study published in Nature Methods utilized a novel and highly mutagenic lentiviral vector to uncover
genes that are involved in hepatocellular carcinoma (HCC) development. Four cancer genes were identified and validated as “altered genes” in HCC samples isolated from patients. This innovative approach
should help identify new prognostic markers and new therapeutic targets for this and perhaps other relevant human cancers (Ranzani et al., Nat Methods 2013; 10:155-161).
• A study published in Immunity identified specific multipotent mesodermal precursors that give rise to different stromal cell subsets of the spleen and support injury-induced regeneration. These results begin
to define the cellular mechanisms responsible for the generation of stromal diversity in secondary lymphoid organs and for the remodeling of lymphoid tissue (Castagnaro et al. Immunity: 2013; 38: 782791).
News from Translational and Clinical Research
The vibrant interaction between basic research and clinical areas represents one of the greatest values
of SRSI and, undoubtedly, this is the peculiarity that makes the Institute so unique. In the various chapters included in this scientific report one can follow in detail the lines of research developed in all the laboratories and clinical units of the hospital and understand the deepest sense of their value. All major areas
in medicine and biology, which are actively developed at SRSI, are covered by translational and clinical
research projects.
As mentioned above, top-level research was conducted in the pediatric arena with gene therapy-based
approaches for MLD and WAS. A new paradigm of treatment with excellent results in terms of efficacy,
safety and tolerability was developed.
XV
INTRODUCTION
Scientific Directors’ Introduction
The area of oncology brought in a large number of state-of- the-art areas of research including oncohematology, cancers of the genito-urinary tract, breast cancer and cancers of the digestive system. Namely,
genomics of chronic lymphocytic leukemia, pancreatic islet auto-transplantation for pancreatic cancer, innovative medical treatment for breast cancer, prognostic factors and multimodal therapy for prostate cancer, the relationship between inflammation-immunity and cancer are only a few of the many topics that
were protagonists of our research.
Radiology and Nuclear Medicine contributed significantly in the areas of central nervous system disease,
oncology in almost all systems, cardiovascular medicine.
Laboratory medicine was able to produce top-level research in many areas including pharmacotherapy
of venous thromboembolism and management of infections.
Neuroscience confirmed its leadership with a large number of different research projects in MR imaging,
management of sleep disorders, multiple sclerosis and genomics, management of degenerative disease
of the central nervous system, use of stem cells for different conditions including eye disease.
Cardiovascular research was significant in many areas including percutaneous vs. open surgical management of coronary artery disease and valve disease, pathophysiology of ischemic heart disease, hypertension and heart failure, and management of arrhythmias.
Diabetes has remained a historically proven area of major scientific research, and contributions in the
field of pancreatic islet transplantation and pharmacotherapy for type 2 Diabetes have been substantial.
Last but not least in the area of dentistry research of substantial interest was led in many areas.
It is expected that both translational and clinical research will continue to flourish in the coming years.
INTRODUCTION
Scientific productivity in 2013
In 2013 the number of SRSI scientific publications and the total impact factor continued to rise, as compared to data from previous years. The total number of scientific publications was 1,142, with a total Impact Factor of 6,451.729 (Figure 1). In 2013 more than to 10% of all SRSI publications were in top-level
scientific journals (Impact Factor over 10, Figure 2).
Based on these results, SRSI has been recognized - once more - as the most highly ranked Italian IRCCS
(among the 47 Italian IRCCS) in terms of scientific quality and scientific productivity.
Figure 1. Publications and total Impact Factor of SRSI in the past 4 years
6,451.729
6,118.243
5,467.350
4,624.629
2010
(average IF: 5.558)
Total IF 2010-2013
2011
(average IF: 5.798)
1,142
1,107
943
832
2012
(average IF: 5.527)
2013 *
(average IF: 5.650)
Publications 2010-2013
* based upon IF 2012
Figure 2. % of SRSI publications sorted according to Impact Factor ranges
Percentage of publications
100%
80%
65.3% 65.2%
65.1%
60%
61.0%
40%
27.3% 28.6% 26.9%
24.2%
20%
7.6%
10.4%
7.8%
10.6%
0%
< 5.000
>
_10.000
5.000-9.999
Impact Factor ranges
2010
2011
2012
2013
Highlighting the notion that clinical research is a major strength at SRSI, the 2013 output in clinical trial
activity was simply excellent. The Ethics Committee examined a total of 243 clinical protocols: 110 (45.3
%) sponsored by Pharmaceutical Companies, 72 (29.6%) SRSI investigator initiated trials and 61 (25.1%)
no-profit groups sponsored trials (Figure 3).
XVII
INTRODUCTION
Scientific Directors’ Introduction
Figure 3. Clinical trials evaluated by the OSR Ethics Committee in 2013
Clinical trials evaluated by EC, 2013
72 (29.6%)
110 (45.3%)
61 (25.1%)
Biotechnology Transfer Activity in 2013
The “Office of Biotechnology Transfer” (OBT) acts as the interface between SRSI and the business community. Its mission is to generate value from know-how, intellectual property, technologies and research
facilities. In the last 10 years of activity OBT obtained the following results: 368 sponsored research or industrial collaboration contracts with about 130 biotech/pharmaceutical companies were successfully finalized; 68 licenses/options and evaluation agreements with industrial partners were executed; 135 patent
families (patented technologies) were filed; 47 patent families (corresponding to a total of 221 patents and
patent applications) are alive as of December 2013.
Funding for research activities
As in the past, the Ministry of Health structural funds (Ricerca Corrente) contributed significantly to the
2013 total research revenues of SRSI. Important research revenues were also obtained from external
grants, which were assigned through internationally recognized peer-reviewed processes. Below is a list
of the most representative funding agencies and of their contribution to SRSI (both OSR and FCSR) in
2013.
INTRODUCTION
Contributions from Main Funding Agencies
YEAR 2013
data in €
Ricerca Finalizzata (Ministry of Health)
6,095,030
AIRC (Italian Association for Cancer Research)
4,513,590
EU (European Union)
3.541.731
Other Private Funding Agencies
1,206,305
Telethon Foundation
1,205,492
ISS (Italian National Institute of Health)
977,431
Armenise Harvard Foundation
603,521
Lombardy Region
546,556
MIUR (Ministry of Education, University and Research)
382,215
JDRF (Juvenile Diabetes Research Foundation)
290,962
FISM (Italian Federation for Multiple Sclerosis)
265,220
AICR (Association for International Cancer Research)
185,365
WHO (World Health Organization)
157,526
INAIL (National institute for insurance against industrial injuries)
124,186
Conclusions and future perspectives
The 2013 Scientific Report of SRSI clearly shows that research in all its forms is lively and vibrant.
We would like to take this opportunity to thank Prof. Maria Grazia Roncarolo who acted as Scientific Director until September 2013 and who was instrumental in the organization of the various Research Divisions, Institutes and Centers. This structure is currently being revamped in order to improve the workflow
of research but the overall skeleton, being robust and efficient, will be maintained.
At present the team of the Scientific Directorate has expanded to include Prof. Giuseppe Banfi, General
Director of Fondazione Centro San Raffaele (FCSR) and Dr. Anna Flavia d‘Amelio Einaudi as representative of the CEO of OSR. The first objective of this new team is to serve the scientific community in order
to facilitate the every day work of all scientists and clinicians involved in research activities. Creating liaisons
among different groups to foster the development of new research projects, helping the process of grant
writing, facilitating the entrance of students as active participants in prestigious research groups, supporting educational programs for all those involved in research, also represent targets that we want to hit.
We are convinced that the quality of health care provided to patients is better in hospitals where research
is actively practiced; curing our patients remain our first goal.
Francesco Montorsi
Scientific Director
Luca G. Guidotti
Deputy Scientific Director
XIX
INTRODUCTION
A short visual history of the Institute...
The hospital, 1970
Construction site of Dibit1, 1991
The hospital in the 1990s
Dibit1 in 1992
The hospital today
The Dibit2 project
Work in progress: Dibit2 and the new hospital quarter
Dibit2 today
INTRODUCTION
San Raffaele Scientific Retreat 2013
XXI
INTRODUCTION
San Raffaele Scientific Retreat 2013
INTRODUCTION
Best poster award
Rocco Baccaro
Efficacy of different anti-hypertensive
drugs to reverse coronary microvascular
remodeling in the spontaneously
hypertensive rat
Best paper award
Davide Gabellini
Cabianca, DS; Casà, V; Bodega, B;
Xynos, A; Ginelli, E; Tanaka, Y;
Gabellini, D. A long ncRNA links copy
number variation to a polycomb/trithorax
epigenetic switch in fshd muscular
dystrophy. Cell: 2012; 149(4): 819-831
XXIII
INTRODUCTION
2013 Seminars and Lectures
■
Division of molecular oncology
■
Division of neuroscience
■
Division of metabolic and cardiovascular sciences
■
Division of regenerative medicine, stem cells and gene therapy
■
Division of immunology, transplantation, and infectious diseases
■
Division of genetics and cell biology
■
Center for translational genomics and bioinformatics
■
Experimental imaging Center
■ February 4, 2013
Mechanisms and consequences of NFAT
signaling pathway activation downstream of
PRRs in innate immune cells
Granucci Francesca, Department of
Biotechnology and Biosciences, University of
Milano-Bicocca, Milan
Guest: Paolo Dellabona
■ March 4, 2013
Stochastic gene expression in single
mammalian cells
Nacho Molina, The Institute of
Bioengineering (IBI), Ecole Polytechnique
Fédérale de Lausanne (EPFL), Switzerland
Guest: Samuel Zambrano
■ March 6, 2013
Redox processes in the mammalian
endoplasmic reticulum: sensors,
mechanisms, and consequences
Christian Appenzeller-Herzog, Division of
Molecular & Systems Toxicology, Department
of Pharmaceutical Sciences, University of
Basel, Switzerland
Guest: Eelco Van Anken
■ March 11, 2013
Bone and mineral metabolism: from gene to
treatment to gene
Maria Luisa Brandi, Bone and Mineral
Metabolism Unit, Department of Surgery and
Translational Medicine, University of Florence
Guest: Simone Cenci
March 18, 2013
Chromatin, gene regulation and Cancer
Luciano Di Croce, Center for Genomic
Regulation, ICREA, Spain
Guest: Vania Broccoli & Giovanni Tonon
■ March 18, 2013
Gene expression changes induced by the
HIV-1 TAT protein. Role of the second exon
José Alcami, Centro National de
Microbiología, Instituto de Salud Carlos III,
Madrid, Spain
Guest: Elisa Vicenzi
■ March 18, 2013
Functions of histone H4-K20
methyltransferases in genome replication and
stability, a link with cancer?
Eric Julien, Montpellier Institute of Molecular
Genetics (IGMM) and Montpellier University,
France
Guest: Giovanni Tonon
■ March 21, 2013
The innate function of human IgM memory B
cells: production of secretory IgA in the gut
Carsetti Rita, B-cell development Unit,
Immunological Diagnosis Unit, Bambino Gesù
Children Hospital, Rome
Guest: Paolo Dellabona
■ March 25, 2013
Che-1 inhibiting mTor pathway in response to
cellular stress sustains autophagy and multiple
myeloma cells growth
Maurizio Fanciulli, Epigenetic Laboratory,
Regina Elena Cancer Institute, Rome
Guest: Giovanni Tonon
INTRODUCTION
■ March 28, 2013
The liver: a site of primary activation leading to
tolerance?
Patrick Bertolino, Liver Immunology group,
Centenary Institute in Sydney, Australia
Guest: Luca G. Guidotti
■ July 16, 2013
Tuberous sclerosis complex, sometimes it
takes a zoo
Kevin Ess, Vanderbilt University, Nashville,
Tennessee, USA
Guest: Rossella Galli
■ April 08, 2013
Mechanisms of myelination in the central
nervous system
Michael Simons, Experimental Medicine,
Max Planck Institute, Göttingen, Germany
Guest: Alessandra Bolino
■ July 22, 2013
The ion channel CFTR as a platform for
protein kinase cross-talk: the ins and outs of
CFTR signalling
Anil Mehta, CVS Diabetes Lung, Ninewells
Hospital and Medical School, University of
Dundee, UK
Guest: Luigi Maiuri
■ April 15, 2013
How integrins control cell fate decisions and
the orientation of polarity in epithelia
Charles Streuli, Wellcome Trust Centre for
Cell-Matrix Research, University of
Manchester, UK
Guest: Ivan De Curtis
■ April 15, 2013
Revealing how WASp stings in
immunodeficiency
Lisa Westerberg, Department of Medicine,
Translational Immunology Unit, Karolinska
Institutet, Stockholm, Sweden
Guest: Anna Villa
■ April 17, 2013
Scurvy is the cost to pay for a defective
oxidative folding
Ester Zito, Metabolic Research laboratory,
University of Cambridge, UK
Guest: Roberto Sitia
■ April 29, 2013
Regulation of normal and leukemic human
stem cells
Tsvee Lapidot, Department of Immunology,
Edith Arnoff Stein Professorial Chair in Stem
Cell Research, Weizmann Institute of Science,
Israel
Guest: Luigi Naldini
■ May 27, 2013
Neuronal endosomes: powerful sorting
stations in health and disease
Bettina Winckler, Department of
Neuroscience, University of Virginia, USA
Guest: Alessandra Bolino
■ July 22, 2013
Prevention of HIV transmission: what can we
learn from non human primate studies
Roger Le Grand, CEA - Division of
Immunovirology, IDMIT and University Paris
Sud, France
Guest: Gabriella Scarlatti
■ September 19, 2013
Transcriptional control of glutamatergic
differentiation during adult neurogenesis
Rebecca Hodge, Center for Integrative Brain
Research, Seattle Children’s Research
Institute, USA
Guest: Francesco Bedogni
■ September 23, 2013
Genetic and non genetic determinants drive
tumor heterogeneity
John Dick, Department of Molecular
Genetics, University of Toronto, Canada
Guest: Luigi Naldini
■ October 03, 2013
DNA methylation shapes the Polycomb
landscape
Richard Meehan, MRC Human Genetics
Unit (HGU), University of Edinburgh, UK
Guest: Davide Gabellini
■ October 07, 2013
The synapsins: alterations of release dynamics
and synaptic plasticity in neuro-psychiatric
disorders
Fabio Benfenanti, Department of
Neuroscience and Brain Technologies,
University of Genova Medical School
Guest: Flavia Valtorta
XXV
INTRODUCTION
2013 Seminars and Lectures
■ October 07, 2013
Advanced optical imaging for biology and
medicine
Gianluca Valentini, Politecnico di Milano
Guest: Davide Mazza
■ October 28, 2013
Regulation of cancer cell motility and
adhesion by integrins and intracellular
adapters
Bernhard Wehrle-Haller, Department of Cell
Physiology and Metabolism, University of
Geneva, Switzerland
Guest: Ivan de Curtis
■ November 04, 2013
Quantitative imaging of hematopoietic stem
and progenitor cell localization and hypoxic
status in the bone marrow microenvironment
César Nombela-Arrieta, Experimental
Hematology Department, University Hospital
Zurich, Switzerland
Guest: Matteo Iannacone
■ November 18, 2013
Aquaporins: a never ending story of new
isoforms and surprising regulations and
functions
Gerd Patrick Bienert, Department of
Physiology and Cell Biology, Leibniz Institute
of Plant Genetics and Crop Plant Research,
Gatersleben, Germany
Guest: Roberto Sitia
■ November 22, 2013
KRAB’n’KAP: from the control of mobile
genetic elements to the regulation of
mammalian homeostasis
Didier Trono, School of Life Sciences, Ecole
Polytechnique Fédérale de Lausanne and
“Frontiers in Genetics” National Center of
Competence in Research, Switzerland
Guest: Luigi Naldini
■ November 25, 2013
Minimising transplant immunosuppression by
the harnessing of tolerance mechanism
Herman Waldmann, Sir William Dunn School
of Pathology, Oxford University
Guest: Anna Mondino
■ December 02, 2013
Ciliary trafficking and epithelial cell polarity
defects as pathophysiological mechanisms in
Nephronophthisis and associated ciliopathies
Sophie Saunier, Université Paris DescartesHôpital Necker-Enfants Malades, France
Guest : Alessandra Boletta
■ December 05, 2013
Blocking IL-1 in a broad spectrum of
inflammatory diseases
Charles Dinarello, University of Colorado,
Denver, USA
Guest: Roberto Sitia
■ December 09, 2013
The new mesenchymal stem cell
Arnold Caplan, Skeletal Research Center,
Case Western Reserve University, Cleveland,
USA
Guest: Massimo Candiani
■ December 10, 2013
Life without H3K9 methylation: loss of
heterochromatin and genome stability
Susan Gasser, Friedrich Miescher Institute for
Biomedical Research, Basel, Switzerland
Guest: Davide Gabellini
XXVI
SCIENTIFIC REPORTS
La “Squadra”
The Scientific Director, the Deputy Scientific Director, and the past Scientific Director,
the Directors and Associated Directors of the Research Divisions and Centers,
and the Directors of the Institutes
1
Divisions, Centers, Institutes and Research programmes
DIVISION OF
MOLECULAR
ONCOLOGY
DIVISION OF
NEUROSCIENCE
URI
UROLOGICAL RESEARCH
INSTITUTE
INSPE
INSTITUTE OF EXPERIMENTAL
NEUROLOGY
Microenvironment
and Genes in Cancers
of the Blood
(MAGIC)
Human Brain Invivo
Mapping with
neuroimaging
(BRAINMAP)
DIVISION OF
METABOLIC AND
CARDIOVASCULAR
SCIENCES
Brain Regeneration
usIng medical
Devices, Gene vectors
and stEm cells
(BRIDGE)
DIVISION OF
REGENERATIVE
MEDICINE, STEM
CELLS AND GENE
THERAPY
HSR-TIGET
THE SAN RAFFAELE-TELETHON
INSTITUTE FOR GENE THERAPY
DIVISION OF
IMMUNOLOGY,
TRANSPLANTATION
AND INFECTIOUS
DISEASES
DIVISION OF
Program in
Immunology and
Bio-immunotherapy
of Cancer (PIBIC)
DRI
DIABETES RESEARCH
INSTITUTE
Islet Trasplantation
Program (ITP)
GENETICS AND
CELL BIOLOGY
CENTER FOR
TRANSLATIONAL
GENOMICS AND
BIOINFORMATICS
IMAGING
EXPERIMENTAL CENTER
Correlates of
HIV-Associated
Immune Response
Modulation
Program (CHARM)
Bone Physiopathology
Program (BoNetwork)
3
DIVISION
OF
MOLECULAR ONCOLOGY
Director:
Federico Caligaris-Cappio*
Associate Director:
Giorgio Parmiani
Research Units
Lymphoid malignancies Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 12
HEAD OF UNIT: Federico Caligaris-Cappio*
POST-DOCTORAL FELLOWS: Benedetta Apollonio (since November 2013), Maria Teresa
Sabrina Bertilaccio, Cristina Scielzo
PHD STUDENT: Benedetta Apollonio**(until October 2013)
FELLOW: Elisa ten Hacken
TECHNICIANS: Federica Barbaglio, Pamela Ranghetti
Biology of multiple myeloma ––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 12
GROUP LEADER: Marina Ferrarini
POST-DOCTORAL FELLOW: Daniela Belloni
Cell activation and signalling –––––––––––––––––––––––––––––––––––––––––––––––––––––––– 13
GROUP LEADER: Marta Muzio
FELLOWS: Eleonora Fonte, Maria Giovanna Vilia
VISITING FELLOW: Stavroula Ntoufa
Tumor microenvironment ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 13
GROUP LEADER: Elisabetta Ferrero
POST-DOCTORAL FELLOW: Daniela Belloni
Immuno-biotherapy of melanoma and solid tumors Unit ––––––––––––––––––––––––––––– 14
HEAD OF UNIT: Giorgio Parmiani
RESEARCHER: Cristina Maccalli (until October 2013)
PHYSICIAN: Carolina Cimminiello
POST-DOCTORAL FELLOW: Elisabetta Zambon
TECHNICIANS: Filippo Capocefalo, Nathascia Chiodo
5
DIVISION OF MOLECULAR ONCOLOGY
Research Units
Cancer gene therapy –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 15
GROUP LEADER: Vincenzo Russo
POST-DOCTORAL FELLOWS: Raffaella Fontana, Laura Raccosta, Matias Soncini
PHD STUDENTS: Marta Moresco**, Aida Paniccia**
TECHNICIAN: Daniela Maggioni
B-cell neoplasia Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 15
HEAD OF UNIT: Paolo Ghia*
POST-DOCTORAL FELLOWS: Andreas Agathangelidis, Claudia Fazi
PHD STUDENTS: Maria Gounari, Giorgia Simonetti
FELLOW: Lydia Scarfò**
TECHNICIAN: Tania Veliz Rodriguez
Functional genomics of cancer Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––– 16
HEAD OF UNIT: Giovanni Tonon
POST-DOCTORAL FELLOWS: Michela Frenquelli, Manuela Occhionorelli, Beatrice Rondinelli,
Simona Segalla
PHD STUDENTS: Marco Gaviraghi**, Alessio Lupi**, Benedetta Santoliquido**
TECHNICIAN: Elena Antonini
INFORMATICIAN: Stefano Ventura
Lymphoid organ development Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––– 17
GROUP LEADER: Andrea Brendolan
POST-DOCTORAL FELLOWS: Elisa Lenti, Monika Wozinska
FELLOWS: Diego Farinello, Maria Teresa Palano**
Molecular histology and cell growth Unit –––––––––––––––––––––––––––––––––––––––––––––––– 18
HEAD OF UNIT: Stefano Biffo
POST-DOCTORAL FELLOWS: Daniela Brina, Piera Calamita, Elia Ranzato, Sara Ricciardi
PHD STUDENTS: Simone Gallo**, Elisa Pesce
FELLOWS: Marilena Mancino, Stefania Oliveto, Jianglin Tan
TECHNICIAN: Annarita Miluzio
Preclinical models of cancer Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 18
GROUP LEADER: Rosa Bernardi, Armenise-Harvard Career Development Award
POST-DOCTORAL FELLOW: Nadia Coltella
PHD STUDENTS: Manfredi Ponente**, Roberta Valsecchi
Tumor biology and vascular targeting Unit –––––––––––––––––––––––––––––––––––––––––––––– 19
HEAD OF UNIT: Angelo Corti
RESEARCHER: Flavio Curnis
FELLOW: Mimma Bianco
TECHNICIANS: Barbara Colombo, Anna Gasparri, Angelina Sacchi
DIVISION OF MOLECULAR ONCOLOGY
Clinical Research Units
Clinical oncology Unit
HEAD OF UNIT: Eugenio Villa
Digestive and pancreatico-biliary endoscopy Unit ––––––––––––––––––––––––––––––––––––– 20
HEAD OF UNIT: Pier Alberto Testoni*
PHYSICIANS: Giulia Martina Cavestro*, Lorella Fanti, Alberto Mariani, Edi Viale
RESIDENTS: Matteo Alessandri , Milena Di Leo, Giorgia Mazzoleni, Chiara Notaristefano,
Gemma Rossi, Raffaella A. Zuppardo
FELLOW: Marco Le Grazie
Endosonography: diagnostic and therapeutic endoscopic ultrasound ––––– 20
CLINICAL GROUP LEADER: Paolo Giorgio Arcidiacono
PHYSICIANS: Emanuele Dabizzi, Maria Chiara Petrone
RESIDENT: Sabrina G. Testoni
FELLOW: Maria Emilia Traini
Gastrointestinal surgical oncology Unit –––––––––––––––––––––––––––––––––––––––––––––––––– 21
HEAD OF UNIT: Gianfranco Ferla* ad interim, since November 2013; Carlo Staudacher*
until October 2013
PHYSICIANS: Paola De Nardi, Saverio Di Palo, Elena Orsenigo, Andrea Marco Tamburini,
Andrea Vignali
RESIDENTS: Massimiliano Bissolati**, Damiano Chiari**, Guido Fiorentini**, Paolo Giovanni
Gazzetta**, Francesca Muffatti**
Head and neck oncology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 21
HEAD OF UNIT: Mario Bussi*
PHYSICIANS: Stefano Bondi, Leone Giordano, Francesca Lira Luce, Matteo Trimarchi
CONSULTANTS: Giulia Danè, Francesca Palonta
RESIDENTS: Matteo Biafora, Davide Di Santo, Francesco Pilolli, Daniela Sarandria, Salvatore
Toma
TECHNICIANS: Daniela Gherner, Barbara Ramella
Multidisciplinary group for thoracic surgical oncology ––––––––––––––––––––––––––––––– 22
HEAD OF UNIT: Piero Zannini*
PHYSICIANS: Alessandro Bandiera, Angelo Carretta, Paola Ciriaco, Giulio Melloni, Giampiero
Negri*, Armando Puglisi
RESIDENTS: Piergiorgio Muriana, Silvia Raimondi Cominesi, Stefano Viscardi
Oncogenesis in liver neoplasms Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––– 23
HEAD OF UNIT: Gianfranco Ferla*
PHYSICIAN: Marco Catena
CONSULTANT: Mvunde Mukenge
RESIDENTS: Federica Cipriani**, Francesca Ratti**
Pancreatic cancer Unit: biology and new therapeutic approaches ––––––––––––––––– 23
HEAD OF UNIT: Gianpaolo Balzano
RESIDENTS: Giovanni Luigi Capretti**, Cristina Gilardini**
FELLOW: Jacopo Nifosi
7
DIVISION OF MOLECULAR ONCOLOGY
Clinical Research Units
Pathology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 24
HEAD OF UNIT: Claudio Doglioni*
PHYSICIANS: Giacomo Dell’Antonio, Massimo Freschi, Roberta Lucianò, Federica Pedica,
Maurilio Ponzoni, Nathalie Rizzo, Francesca Sanvito, Isabella Sassi
BIOLOGISTS: Maria Giulia Cangi, Lorenza Pecciarini
PHD STUDENTS: Daniela Clavenna, Valeria De Pascale, Greta Grassini, Gilda Magliacane
FELLOWS: Francesca Invernizzi, Lara Mainetti
TECHNICIANS: Elena Dal Cin, Stefano Grassi, Anna Innocenzi, Martina Rocchi, Graziella
Santambrogio, Anna Talarico
Clinical lymphoid malignancies –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 24
HEAD OF UNIT: Federico Caligaris-Cappio*
CLINICAL GROUP LEADER: Andrés José Marìa Ferreri
PHYSICIANS: Giovanni Donadoni, Giovanni Citterio, Marco Foppoli, Marianna Sassone, Lydia
Scarfò
RESIDENTS: Antonella Capasso, Chiara Giudice, Gabriele Todisco, Alessandro Vignati
DATA MANAGERS: Eleonora Piraino, Costanzo Sarracino, Eloise Scarano
Gynecologic oncology –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 25
HEAD OF UNIT: Massimo Candiani*
CLINICAL GROUP LEADER: Giorgia Mangili
PHYSICIANS: Patrizia De Marzi, Davide Ferrari, Emanuela Rabaiotti, Micaela Petrone
RESIDENTS: Alice Bergamini, Veronica Giorgione, Jessica Ottolina, Francesca Pella, Cristina
Sigismondi
Medical oncology Unit
HEAD OF UNIT: Luca Gianni
Clinical trials –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 26
CLINICAL GROUP LEADER: Michele Reni
PHYSICIANS: Stefano Cereda, Elena Mazza
CONSULTANT: Carmen Belli
RESEARCH NURSE: Domenica Ceraulo
Phase I and lung cancer clinical trials ––––––––––––––––––––––––––––––––––––––––––––– 26
CLINICAL GROUP LEADER: Vanesa Gregorc
PHYSICIANS: Alessandra Bulotta, Maria Grazia Viganò
Onco-hematology ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 27
HEAD OF UNIT: Fabio Ciceri
CLINICAL GROUP LEADER: Massimo Bernardi
PHYSICIANS: Matteo Carrabba, Fabio Giglio, Elena Guggiari, Francesca Lunghi, Magda
Marcatti
RESIDENTS: Carlo Messina**, Elisa Sala**
STUDY COORDINATOR: Stefania Trinca
RESEARCH NURSE: Margherita Brambilla
DATA MANAGER: Ambra Malerba
TECHNICIAN: Fernanda Tripiciano
DIVISION OF MOLECULAR ONCOLOGY
URI
Urological Research Institute
Director (ad interim):
Francesco Montorsi*
Research Units
Urological pre-clinical research Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––– 29
HEAD OF UNIT: Petter Hedlund
PHYSICIANS: Umberto Capitanio, Federico Dehò, Massimo Freschi, Andrea Gallina, Roberta
Lucianò, Nazareno Suardi
RESIDENTS: Paolo Capogrosso**, Fabio Castiglione**, Paolo Dell’Oglio**, Ettore Di Trapani**,
Nicola Fossati**, Giorgio Gandaglia**, Giovanni La Croce**, Alessandro Nini**, Lorenzo
Rocchini**, Andrea Russo**, Manuela Tutolo**, Luca Villa**
POST-DOCTORAL FELLOW: Ilaria Cavarretta
TECHNICIANS: Arianna Bettiga, Giorgia Colciago, Anna Maria Ferrara
Functional urology ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 29
GROUP LEADER: Fabio Benigni
PHYSICIANS: Federico Dehò, Andrea Gallina, Alessandro Mistretta, Nazareno Suardi
RESIDENTS: Fabio Castiglione**, Ettore di Trapani**, Nicola Fossati**, Giorgio
Gandaglia**, Giovanni La Croce**, Alessandro Nini**, Andrea Russo**, Luca Villa**
POST-DOCTORAL FELLOW: Roberta Buono
TECHNICIANS: Arianna Bettiga, Giorgia Colciago, Anna Maria Ferrara
Clinical Research Units
Prostate cancer ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 30
HEAD OF UNIT: Francesco Montorsi
CLINICAL GROUP LEADER: Alberto Briganti
PHYSICIANS: Firas Abdollah, Umberto Capitanio, Andrea Gallina, Giovanni Lughezzani,
Vincenzo Scattoni, Nazareno Suardi
RESIDENTS: Marco Bianchi**, Fabio Castiglione**, Paolo Dell’Oglio**(since August
2013), Ettore Di Trapani**, Nicola Fossati**, Giorgio Gandaglia**, Alessandro Larcher**,
Giuliana Lista**, Alessandro Nini** (since August 2013), Manuela Tutolo**, Luca Villa**
DATA MANAGERS: Elena Farina, Nadia Finocchio, Marta Picozzi
9
DIVISION OF MOLECULAR ONCOLOGY
Clinical Research Units, URI
Bladder cancer Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 30
HEAD OF UNIT: Renzo Colombo
PHYSICIANS: Nazareno Suardi, Giuseppe Zanni
RESIDENTS: Paolo Capogrosso**, Giovanni La Croce**, Lorenzo Rocchini**
POST-DOCTORAL FELLOW: Marco Moschini
DATA MANAGER: Giusy Burgio
Renal cancer Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 31
HEAD OF UNIT: Roberto Bertini
PHYSICIANS: Umberto Capitanio, Ryan Matloob
RESIDENTS: Fabio Castiglione**, Ettore Di Trapani**, Andrea Russo**
DATA MANAGER: Cristina Carenzi
Sexual medicine Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 31
HEAD OF UNIT: Andrea Salonia
RESIDENTS: Paolo Capogrosso**, Giulia Maria Castagna (since August 2013), Fabio
Castiglione**, Giovanni La Croce**
DATA MANAGER: Donatella Moretti
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
DIVISION OF MOLECULAR ONCOLOGY
Introduction by the Directors
Mission and vision - to overcome the biological barriers that prevent clinical advances in the treatment of
cancer innovative strategies are needed in the areas of diagnosis, patient risk stratification and treatment.
Along this line we are building onto two fundamental concepts:
1) cancer is a collection of many diseases most requiring specialized research, diagnostic and treatment;
2) the development of new treatment strategies depends on the seamless and multi-disciplinary interaction between researchers and specialized clinicians. Accordingly we are fostering extensive collaborations between basic scientists and clinicians and improving international connections to develop
translational and clinical research programs.
Organization - The Division is organized into Basic Research Units (URB) and Groups of Clinical Research
(GRC) trying to funnel their activities into Research Programs. Overall the Personnel is close to 190 people. The Lab space allocated to the Division is about m2 1800. To favor a more mature organization we
are developing, together with Clinical Departments and other Research Divisions, infrastructure facilities
that include an annotated data base of patients with blood tumors linked to a bio-bank (in collaboration
with the Dept of Pathology). We have also established mouse and cell line registers.
Goals - The scientific goals of the Division are based on the approach “build on strength”. Two major areas
of excellence have been identified: Cancer Microenvironment and Cancer Immunology and Immunotherapy. The scientific aims within these areas have been directed into two specific Research Programs, Microenvironment and Genes in Cancers of the Blood (MAGIC) and Immunology and
Bio-Immunotherapy of Cancer (PIBIC), which span from basic science to clinical application and focus
on specific malignancies for which we are internationally renowned. Moreover Dr Luca Gianni and his
group have opened a new perspective in the development of Phase I clinical trials and the investigation
of Breast Cancer, Prof F. Montorsi and his group are focusing onto the investigation of Prostate Cancer.
Achievements - MAGIC bridges the Division of Molecular Oncology with the Clinical Department of OncoHematology, entails the participation of numerous other Research Divisions and is essentially centered
upon Chronic Lymphoid Malignancies. The program combines and compares the genetic and microenvironment analysis into a fully integrated genotype-phenotype and tumor-microenvironment scientific approach utilizing a whole range of mouse models, many established by different members of the Division.
We expect to translate the findings into a comprehensive blueprint for the risk stratification of individual
patients and to develop novel therapeutic strategies based upon new molecular targets.
PIBIC is co-organized with the Division of Immunology, its scientific theme being an Institutional historical
strength. PIBIC’s focus is the role of the immune system and of its manipulation in specific cancers, especially melanoma and epithelial cancers. The basic/pre-clinical results start to be translated into novel,
proof of principle clinical trials.
Training Opportunities - The Division hosts the Section of Biology and Biotherapy of Cancer which is part
of the Institutional PhD Program in Molecular Medicine, offers numerous post-doc opportunities at national
and international level and is well prepared to host, train and mentor Physician Scientists.
11
DIVISION OF MOLECULAR ONCOLOGY
Research Units
Lymphoid malignancies Unit
Monocyte/macrophage lineage cells significantly influence the survival
and proliferation of CLL cells in mouse models
The development and progression of CLL are dependent upon a complex microenvironmental network of cellular and molecular signals. As an example, the in vitro survival of CLL cells is supported
by nurse-like cells, which have been identified as a
CLL-specific tumor-associated macrophage (TAM)
population. However little is known regarding the
role of TAMs in CLL development and progression.
We characterized the macrophage composition in
two CLL mouse models: a) a xenograft model
based on the engraftment of the MEC1 human
CLL cell line into Rag2-/-gc-/- mice; and b) the
TCL1 transgenic mouse model of CLL. We analyzed the whole-genome transcriptome of TAMs
and leukemic B cells isolated from the bone marrow of MEC1-bearing mice and found an enrichment of genes involved in inflammation and interaction between TAMs and B-cells. We then
employed an in vivo macrophage killing approach
based on liposome-mediated internalization of clodronate (clodrolip) by macrophages. We trans-
planted Rag2-/-gc-/-mice intravenously (i.v.) with
MEC1 cells and depleted macrophages by i.v. clodrolip delivery. Macrophage depletion resulted in a
drastically reduced accumulation of CLL cells in all
tissues. Moreover, when C57BL/6 mice were
transplanted with leukemic cells from TCL1 transgenic mice and macrophage-depleted, significantly
fewer leukemic B cells were detected in the lymphoid tissues analyzed. Finally, to explore the possibility that manipulating leukemic cell/macrophage
interactions might be exploited as a potential novel
therapeutic strategy, Rag2-/-gc-/- animals transplanted subcutaneously with MEC1 cells and carrying visible leukemic lymph nodes (LN) were injected with clodrolip in the proximity of the LNs. This
treatment drastically reduced LN size and
favourably impacted on the overall mouse survival.
In summary, our data open up novel therapeutic avenues for CLL based on interfering with leukemicmacrophage interactions.
Federico Caligaris-Cappio
Biology of multiple myeloma
Role of angiopoietins in multiple myeloma-associated angiogenesis
Our Unit is investigating the role of Bone Marrow
(BM) microenvironment, and particularly of BMassociated vasculature, in Multiple Myeloma (MM)
biology and progression, to identify biomarkers
and possibly new therapeutic targets.
The Tie-2/Angiopoietins (Ang) receptor-ligand axis
has been recognized as a key regulator of angiogenesis in both solid tumors and haematological
malignancies. In MM, serum Ang-2 correlates
with disease progression and response to therapy. Ang-1 and Ang-2 are the major members of
the Angiopoietin family and exert antagonistic
roles in angiogenesis, via the competitive binding
to the common tyrosine kinase receptor Tie-2 on
endothelial cells (EC). In particular, Ang-1 ensures
vascular stability, while Ang-2 destabilizes neoforming vessels.
In collaboration with Elisabetta Ferrero (Tumor Microenvironment Unit), we are assessing expression and pro-angiogenic functions of Angs in MM.
Ang-2 levels in the BM allowed to discriminate patients with active disease, suggesting a pathogenetic role for the molecule. Accordingly, MM
BM sera with high Ang-2 concentration specifically contributed to EC activation in vitro, while Ang-1
containing sera maintained EC stabilization/proliferation. The functional dichotomy of Ang-1 and
Ang-2 was confirmed by the triggering of distinctive pathways of Tie-2 phosphorylation and downstream signaling through the Akt or the ERKphosphorylation pathway. Notably, Ang-2 but not
VEGF serum levels correlated with BM micro-vessel density, further underscoring the key role of
Ang-2 in dictating angiogenesis. Western Blot,
RT-PCR analysis and immunocytochemistry identified MMEC as the major source of Ang-2 inside
the BM, at variance with MM cells, BM stromal
cells and CD14+ BM monocytes. These data indicate that Ang-2 produced in the BM milieu contributes to MM angiogenesis in vitro and in vivo
and suggest that the molecule can be further exploited both as angiogenesis biomarker and as a
potential therapeutic target.
We next plan to determine the prognostic value of
Angs, in association with other angiogenic molecules, in MM. This might help to define an “angiogenic profile” of MM patients and in turn allow the
identification of patients who could benefit from
targeted anti-angiogenic approaches.
Marina Ferrarini
DIVISION OF MOLECULAR ONCOLOGY
Cell activation and signalling
Toll-like receptors in chronic lymphocytic leukemia
Chronic Lymphocytic Leukemia (CLL) is a heterogeneous disease characterized by the accumulation of small clonal B-lymphocytes in the peripheral blood and lymphoid tissues. Several lines of evidence support the hypothesis that, in addition to
specific genetic alterations within leukemic cells,
microenvironmental interactions may also play a
role in the biology of the disease.
Toll like receptors (TLR) are expressed by normal
and leukemic B cells; that notwithstanding, different patients with CLL show different patterns of
expression of TLR and signaling molecules in
leukemic lymphocytes. Previous data suggested
that the stimulation of CLL cells with TLR ligands
can trigger specific signaling pathways and can
regulate the expression of surface molecules and
spontaneous apoptosis.
During 2013 we focused our attention onto
chemoresistance; we hypothesized that TLR
stimulation could modify the response of CLL
cells to subsequent drug treatment in vitro. We
isolated leukemic cells from the peripheral blood
of CLL patients, and cultured them with or without
the addition of specific TLR ligands; following, we
treated the cells with fludarabine, and we analyzed cell viability, apoptosis and molecular pathways involved.
Heterogeneity was observed among samples,
and TLR stimulation caused a significant protection to fludarabine treatment in leukemic cells isolated from patients bearing adverse prognostic
factors. To identify which molecular mechanisms
accounted for this heterogeneous response, we
performed an RT-PCR apoptosis gene expression
array on leukemic cells either unstimulated or
stimulated with TLR9 ligand. Strikingly, TLR9 stimulation upregulated the expression of lymphotoxin-α and miR155-3p specifically in “chemoresistant” cells which resulted protected from in vitro
fludarabine treatment.
These results help to better understand the specific contribution of distinct TLR within distinct
groups of CLL samples, and suggest that among
microenvironmental interactions TLR ligands may
play a role in CLL pathobiology and chemoresistance.
Marta Muzio
Tumour microenvironment
Ex-vivo dynamic culture in bioreactor of human MM samples and MM cellsseeded scaffolds allows the study of MM biology and response to drugs
Multiple Myeloma (MM) cells depend on the interactions with the Bone Marrow (BM) microenvironment for their survival and progression. Accordingly, a better understanding of MM biology and
response to drugs require the existence of human
models able to properly reflect the dynamic complexity and spatial organization of the native milieu.
In collaboration with Marina Ferrarini (Unit of MM
Biology), we have recently developed and validated a human, dynamic model of culture in RCCS
TM, suitable to keep in culture MM samples for
up to two weeks; samples maintained their viability and intact overall architecture, including vasculature and bone lamellae. This technology allowed
also to monitor over time specialized functions of
MM cellular components, in particular vessels,
and, notably, to assess response to drugs. As an
alternative to the use of MM samples, we are now
exploiting the Bioreactor technology as a tool to
support the reconstruction of a MM-associated
microenvironment. The reconstruction is based
on the use of selected scaffolds pre-seeded with
cellular components of MM microenvironment,
namely endothelial cells and BM stromal cells, to
be repopulated with MM cells. The integrated use
of scaffolds and Bioreactor sustains an efficient
cellular pre-seeding and MM viability, proliferation
and specialized functions for weeks. Our final
achievement is to recreate an autologous, patient-derived system, for the identification of personalized therapies.
Elisabetta Ferrero
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DIVISION OF MOLECULAR ONCOLOGY
Research Units
Figure 1. Scanning Electron Microscopy (SEM) analysis of scaffolds populated with endothelial cells and myeloma
cells and cultured in RCCS TM bioreactor (in collaboration with Consorzio MIA).
Immuno-biotherapy of melanoma and solid tumors Unit
During 2013, the research activity of our Unit has
been focused on:
1. Pre-clinical work
• Mutated antigens of colorectal cancer (CRC).
During last year we have continued and concluded the first part of our project aimed at testing the immunogenicity of somatically mutated
new CRC antigens, previously identified by sequence analysis of the mutations of CRC cells
and of their cancer stem cells (CSC). This work
involves the collaboration with the Unit of Exp.
Immunology (P. Dellabona) within the framework
of the PIBIC.
• Cancer Stem Cells. CSC have been isolated in
vitro from glioblastoma and CRC and their immune profile defined. We have previously
shown that CSC of human glioblastoma may be
immune-suppressive. In the 2013 we have
identified potential mechanisms of such a phenomenon, in the CSC-mediated activation and
release of the indolamine 2,3-dioxigenase by
cancer cells, and by expression of IL-4 by
CSCs.
• Immune monitoring of melanoma patients treat-
ed with kynase inhibitors or ipilimumab. In collaboration with other groups (M. Maio, Siena; L.
Rivoltini, Milan) we have analyzed the phenotype
and function of patients’ T cells before, during
and after therapy in order to identify immune
biomarkers associated with the clinical response. It was found that a large fraction of
melanoma pts who have received ipilimumab
show an increased T cell response against defined melanoma antigens.
2. Clinical studies
• Adoptive immunotherapy of melanoma. New
studies allowed to identify the best procedure of
in vitro expansion for patients’ anti-tumor T cells.
In 2013 we have validated the procedure of T
cell preparation under GMP in 3 cases as requested by Italian regulatory authorities. The
dossier to be submitted to AIFA is an advanced
stage of preparation. A new PI (Dr. Jacopo Peccatori) was recruited since Dr. Parmiani retired
from OSR at the end of 2013; a re-evaluation of
the different aspects of the project is ongoing to
allow to initiate the clinical trial.
• A new protocol based on the combination of
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NGR- hTNF and peptide vaccine has been
closed; 8 pts have concluded the treatment
program. Immune response to the vaccine and
to other melanoma antigens (antigenic spread)
has been found partly associated with the clinical outcome.
• Another spontaneous trial combining Ipilimumab
and Fotemustine was approved for metastatic
melanoma; the patients accrual was closed in
March 2012. Results were collected during the
first part of the 2013 and then published in
Lancet Oncology.
Giorgio Parmiani
Cancer gene therapy
It is recognized that the formation of human cancers requires the progressive acquisition of oncogene activating mutations and oncosuppressor
alterations of normal cells, together with the establishment of immunosuppressive networks
within the tumor microenvironment. In recent
years, several and distinct immunosuppressive
mechanisms dampening antitumor immune responses have been characterized. These mechanisms play a key role in affecting antitumor immune responses, as demonstrated by recent
clinical experiences with immune checkpoint
blocking antibodies (i.e., anti-CTLA4 and anti-PD1 monoclonal antibodies), which have prolonged
the overall survival of metastatic melanoma patients. Our group has recently identified a mechanism of immune escape based on the release by
tumor cells of metabolites of cholesterol, namely
oxysterols (Traversari and Russo. Curr. Op. Pharmacol, 2012). These molecules and their receptors (i.e., Liver X Receptors), primarily identified as
regulators of cholesterol homeostasis, are currently recognized as pleiotropic and multifaceted
molecules controlling several functions of immune
cells. In this context, we have shown that tumorderived oxysterols inhibit the antitumor immune
response by recruiting pro-tumor neutrophils within the tumor microenvironment (Raccosta et al. J.
Exp. Med, 2013). Recruited neutrophils promote
tumor growth by inducing neo-angiogenesis or by
suppressing antigen-specific T cells. Notably, the
use of drugs interfering with oxysterol generation
restores the spontaneous antitumor immune response and the control of tumor growth in mouse
tumor models. In addition, we are investigating
new strategies of active immunotherapy to improve antitumor immune responses (Russo et al.
Trends Mol. Med, 2012). We have developed a
novel strategy of active immunotherapy based on
the in vivo loading of antigen presenting cells (i.e.,
dendritic cells) with tumor antigens (Russo et al. J
Clin Invest, 2007). The clinical translation of this
approach led to the development of a clinical protocol showing a favorable correlation between the
increase of antitumor effectors and overall survival
in melanoma patients (Fontana et al. Blood, 2009;
Russo et al. Int. J. Cancer, 2013).
Vincenzo Russo
B-cell neoplasia Unit
Non-random association of novel gene mutations with stereotyped CLL subsets
Recent studies have revealed recurrent mutations
of the NOTCH1, SF3B1 and BIRC3 genes in
chronic lymphocytic leukemia (CLL), especially
among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their
presence may differ in subsets of patients carrying stereotyped B-cell receptors and also exhibiting distinct prognoses. During 2013, we analyzed
the mutation status of NOTCH1, SF3B1 and
BIRC3 in three subsets with particularly poor
prognosis, that is, subset #1, #2 and #8, aiming
to explore links between genetic aberrations and
immune signaling. A remarkably higher frequency
of SF3B1 mutations was revealed in subset #2
(44%) versus subset #1 and #8 (4.6% and 0%,
respectively; P<0.001). In contrast, the frequency
of NOTCH1 mutations in subset #2 was only 8%,
lower than the frequency observed in either subset #1 or #8 (19% and 14%, respectively; P=0.04
for subset #1 versus #2). No associations were
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DIVISION OF MOLECULAR ONCOLOGY
Research Units
found for BIRC3 mutations that overall were rare.
The apparent non-random association of certain
mutations with stereotyped CLL subsets alludes
to subset-biased acquisition of genomic aberrations, perhaps consistent with particular
antigen/antibody interactions. These novel find-
ings assist in unraveling specific mechanisms underlying clinical aggressiveness in poor-prognostic stereotyped subsets, with far-reaching implications for understanding their clonal evolution and
implementing biologically oriented therapy.
Paolo Ghia
Cumulative events
Genetic defects in Subsets are not random
Subset 1
Subset 2
Subset 8
Subsets
Ghi
t l Bl
d 2005
Figure 2. Different stereotyped subsets show distinct genetic abnormalities (frequency of somatic mutations on
NOTCH1 and SF3B1 genes). Modified from: Strefford, JC et al., Leukemia: 2013; 27(11): 2196-2199 doi:
10.1038/leu.2013.98
Functional genomics of cancer Unit
Our laboratory is currently pursuing the following
lines of research:
1. Role of histone methylation and demethylation
in cancer development
In the nuclei of eukaryotic cells, DNA is packed into
chromatin. The basic constituent of chromatin, the
nucleosome, is comprised of 147bp of DNA
wound around an octamer of core histone proteins.
Post-translational modifications of the N-terminal tails
of these core histone proteins, modulate chromatin
configuration, resulting in changes in transcriptional regulation. These epigenetic modifications are con-
trolled by complex enzymatic machinery that, when
deregulated, disrupt normal transcriptional programs. Indeed, genomic alterations of MLL, NSD1,
CREBBP, WHSC1L1 and WHSC1, all encoding proteins involved in histone modification, have been implicated in several cancer types.
Through genomic analysis and large-scale highthroughput sequencing, we have identified genetic lesions affecting histone methylases and
demethylases and we are exploring the role of the
genes implicated in these genomic rearrangements in the development of multiple myeloma,
lung cancer and renal carcinoma.
DIVISION OF MOLECULAR ONCOLOGY
2. RNA metabolism in cancer
The pathways leading to RNA catabolism are
poorly characterized, and even less their potential
role in cancer. We have identified genetic lesions
affecting genes at the crossroad of various RNA
metabolism pathways. Ongoing experiments are
evaluating their role in dysregulating oncosuppressive and oncogenic mechanisms in cancer
cells.
3. Receptor tyrosine kinase receptors in the development of Multiple Myeloma
The protein kinase is the most commonly represented Pfam domain encoded by cancer genes.
Many carcinogenic tyrosine kinases are receptors, which are often overexpressed and/or mutated in a variety of tumors. Therapeutic agents
targeting this class of receptors have proven to
be highly effective in the clinical setting.
We have conducted a genomic and proteomic
survey of primary multiple myeloma samples, a
deadly hematological cancer and have identified
two overexpressed RTKs. The goal of this project
is to elucidate the nature of the signaling mediated by these RTKs in MM, both in vitro and in vivo,
with the final goal of identifying more effective
drugs against this deadly disease.
Giovanni Tonon
Lymphoid organ development Unit
Development and function of the lymphoid stromal microenvironment
Research in our laboratory focuses on understanding the mechanisms underlying the development of lymphoid organs with emphasis on stromal cells. Current research projects aim:
1. To identify signaling pathways underlying specification of stromal progenitors.
The signaling pathways required for specification
and differentiation of stromal progenitors remain
largely unknown. We use mouse genetics coupled to microarray and ChIP-seq analyses to
identify pathways controlled by spleen and lymph
node-specific transcription factors during early
spleen and lymph node development. We are
currently assessing the contribution of different
signaling pathways in organogenesis of lymphoid
tissues.
2. To uncover the origin of mature lymphoid stromal cells.
The origin of the different stromal cell subsets remains elusive. By performing lineage-tracing
analysis, we demonstrated that spleen, but not
lymph node stromal cells, originate from embryonic Nkx2-5+Isl1+ mesodermal progenitors. This
lineage includes lymphoid tissue organizer cells
capable to promote the formation of artificial lymphoid-like structures with features of native tis-
sues. We discovered that resident stromal cells of
this lineage proliferate and regenerate the stromal
microenvironment following resolution of a viral infection. These findings provided novel mechanistic insights into how stromal diversity originates
and stromal repair occurs, and the basis for developing artificial lymphoid tissues for pre-clinical
applications (Castagnaro et al., Immunity 2013).
We are currently assessing the origin of lymph
node stromal cells.
3. To dissect the role of the stromal microenvironment in leukemia.
It is increasingly clear that stromal cells play a crucial role in B-cell malignancies including chronic
lymphocytic leukemia (CLL) survival and expansion. However, the precise nature of stromal cells
and the mechanism by which these cells contribute to leukemia progression remain unclear.
We performed a comprehensive in vivo analysis
on murine and human CLL biopsies and identified
changes occurring within the stromal compartment during disease progression. We are currently identifying the signaling pathways contributing
to the remodeling of the stromal microenvironment during leukemia progression.
Andrea Brendolan
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DIVISION OF MOLECULAR ONCOLOGY
Research Units
Molecular histology and cell growth Unit
Translational control in cancer
Gene expression is controlled at the level of translation by the combination of Initiation Factors and
RNA binding proteins. It has now emerged that
translational control is altered in tumors and it can
be targeted by specific drugs. Our laboratory has
shown that eIF6 is rate-limiting in tumor formation
by a combination of cellular, biochemical and genetic techniques. In summary, some tumors express high levels of hyperphosphorylated eIF6, and
its targeting results in reduced tumor growth.
Through a combination of High Throughput studies
and specific investigator-driven hypothesis, we
have been able to identify the molecular signature
that accompanies tumorigenesis mediated by eIF6
activation. In parallel, our laboratory has contributed
to the identification of a) translational pathways altered in multiple myeloma, b) new therapeutic
strategies in malignant mesothelioma, and c) new
cellular models for the validation of drugs acting in
a patient specific fashion. In summary, we have
contributed to the new notion that gene expression
is shaped by translational mechanisms that can be
exploited for targeting cancer cells.
Stefano Biffo
Preclinical models of cancer Unit
Role of HIF factors in hematological malignancies
We aim to understand the role of hypoxia-inducible transcription factors (HIF) in hematological
malignancies, and to test the efficacy of their targeting as a novel therapeutic approach in combination with standard therapeutic agents.
HIF factors are often upregulated in solid tumors
because of hypoxia or oxygen-independent
mechanisms, and promote tumor progression by
regulating metabolic adaptive pathways, neo-angiogenesis, cell migration and invasion, and maintenance of cancer stem cells.
In the past year we have terminated earlier studies
where we had identified HIF-1α as a critical proleukemogenic factor in acute myeloid leukemia
(AML), particularly in the M3 subtype acute
promyelocytic leukemia (APL), and in chronic lymphocytic leukemia (CLL). We had found that in
APL cells HIF-1α is functionally activated because
of direct cooperation with the oncogenic fusion
protein PML-RARα while in CLL it is highly expressed at the mRNA level. Inhibition of HIF-1α by
shRNA led to reduced leukemia progression in
both pathologies. However, interestingly HIF-1α
plays different roles in distinct hematopoietic neoplasms: in APL HIF-1α regulates intrinsic and
chemokine-directed cell migration, neoangiogenesis in the bone marrow and leukemia stem cells
self-renewal, while in CLL HIF-1α especially regulates the interaction of leukemic cells with bone
marrow and splenic microenvironments. As a
consequence, inhibition of HIF-1α by compounds
with HIF-inhibitory activity blunted leukemia progression in both pathologies, but in APL it also affected maintenance of leukemia initiating cells
while in CLL it induced the mobilization of CLL
cells from bone marrow and spleen and cooperated with chemotherapeutic compounds in inducing CLL cells apoptosis.
In this past year we have found that in APL expression of HIF-1α is further upregulated by treatment with all-trans retinoic acid (ATRA), the treatment of choice for APL patients. ATRA treatment
does not fully eradicate APL, and in vitro increases clonogenicity of leukemic blasts. We found
that concomitant treatment of APL cells with
ATRA and inhibitors of HIF-1α exquisitely cooperates in reducing leukemia-initiating cells in serial
replating and serial transplantation experiments.
Rosa Bernardi
DIVISION OF MOLECULAR ONCOLOGY
Tumor biology and vascular targeting Unit
Regulation and manipulation of tumor vessels and microenvironment
Our research activities focus on studies of tumor
vascular biology and of the development of new
strategies for cancer therapy based on the manipulation of the tumor vasculature and microenvironment. We have found that peptides containing
the NGR or isoDGR sequences can be exploited
for delivering TNF-α and other cytokines to tumor
vessels and, consequently, for altering the endothelial barrier function and increasing the penetration of chemotherapeutic drugs and infiltration
of lymphocytes in tumors. Because of these
properties, one of these compounds, called
NGR-TNF, is currently tested in various Phase II
and III clinical studies, alone and in combination
with chemotherapy or immunotherapy. Other lines
of research are focused on the role of proteins
containing the NGR, and isoDGR sequences in
tumor vascular biology and angiogenesis. Regarding NGR (asparagine-glycine-arginine) this
sequence is present in many molecules of the extracellular matrix. We have demonstrated that
NGR can undergo rapid deamidation reactions
generating the isoDGR (isoAsp-Gly-Arg) sequence in fibronectin and in other proteins of the
extracellular matrix. This post-translational modification can work as a “molecular switch” for the
time-dependent generation of new binding sites
for integrins. In particular, we have found that peptides and fibronectin fragments containing the
isoDGR motif can bind αvβ3, an integrin expressed in the angiogenic vasculature, can affect
endothelial cell functions and inhibit tumor growth.
We have also developed head-to-tail cyclic isoDGR peptides that can be easily coupled to proteins and gold nanoparticles and demonstrated
that they can be exploited as ligands for delivering
cytokines and nanodrugs to the tumor vasculature. Finally, we have observed that circulating
CgA, a protein secreted by many neuroendocrine
cells and granulocytes, is elevated in patients with
cancer and other inflammatory diseases, can regulate the endothelial barrier function and the TNFinduced vascular leakage, can regulate angiogenesis (by working as an angiogenic switch activated by thrombin), and can reduce tumor cell trafficking and metastasis development in animal
models.
Angelo Corti
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DIVISION OF MOLECULAR ONCOLOGY
Clinical Research Units
Digestive and pancreatico-biliary endoscopy Unit
The unit is involved in the development and clinical application of advanced endoscopic imaging
and endoluminal therapy for recognition and treatment of high grade dysplasia and early cancer of
gastrointestinal tract (G.I.) and pancreatico-biliary
system.
Advanced endoscopic imaging
In these years the research has been focused
mainly on the use of advanced imaging techniques for detecting and characterizing mucosal
and submucosal lesions of gastrointestinal tract
and differential diagnosis of strictures of unknown
aetiology of the main pancreatic and common bile
duct.
Surface and contrast enhancement endoscopy
has been shown effective in the recognition and
treatment of mucosal pre-neoplastic and neoplastic lesions; the technique appears particularly
useful to investigate more accurately Barrett’s
esophagus, gastric dysplasia, colonic flat lesions.
Confocal endomicroscopy is currently used in
clinical practice since the beginning of 2010. It is
a new advanced imaging technique which enables in vivo microscopy with subcellular resolution during ongoing endoscopy. The technique is
very effective in detecting neoplastic lesions at a
very early stage, identifies pre-neoplastic lesions,
and gives information about living cells in human
beings. Confocal endoscopy can be carried out
also by probes that can be inserted into the pan-
creatico-biliary system, during ERCP procedures,
and plays a pivotal role in the endoluminal diagnosis and staging of cholangiocarcinoma.
Endoluminal therapy
Endoscopy is increasingly used for treatment of
neoplastic or pre-neoplastic lesions of the GI tract
confined in mucosa and submucosa layer, since
it allows to remove tissue by mucosal resection,
submucosal dissection, and radiofrequency ablation. Radiofrequency can also be used into pancreatico-biliary ductal system to treat neoplastic
strictures. The unit is involved in the development
of new devices for tissue removal and radiofrequency delivering for both GI tract and pancreatico-biliary system. These devices consent the
complete removal of pre-neoplastic or early neoplastic lesions, and treatment of inflammatory and
neoplastic ductal strictures.
Circulating biomarkers
Biomarkers should be useful in clinical surveillance in digestive diseases, in prevention of malignancy, and recognition of cancers in early
stage. Circulating levels dosage of apoptosis inhibitory proteins and mRNA will be analyzed. In
particular, QSOX-1, survivin, XAF-1 and BCL2 will
be tested in Barrett’s esophagus and gastrointestinal cancer, IPMN, and pancreatic adenocarcinoma.
Pier Alberto Testoni
Endosonography: diagnostic and therapeutic endoscopic
ultrasound
During 2013, our Unit focused on the following
Research Projects:
• EUS-guided cryothermal ablation in patients
with stage III (Locally advanced and borderline
resectable) pancreatic adenocarcinoma. Phase
II/III trial. Grant ERBE gmbh Germany. Local
treatment of pancreatic cancer with vessel infiltration to increase the resection rate was the
end points of a trial on the use of a new prototype of ablation device. The preliminary results
have shown the safety of this device and a
trend in favor of tumor reduction after treatment.
Now a Randomized Controlled Trial was designed to show the efficacy of the probe to increase resection rate of this tumor.
• IPMN branch duct follow up. Multicenter Trial
(Mayo Clinic Charlottsville Principal Investigator)
Adherence of Sendai criteria to the EUS follow
up data in branch duct IPMN. Presentation
Award Best Poster Presentation DDW 2014
Chicago.
• ASPRO Study. Randomized Controlled Trial on
comparison of 20 G pro-core needles vs 25
needles in FNA (Erasmus Rotterdam Principal
Investigator) (Funded by Cook Medical)
• EUS FNA is considered the best modality to target lesions in different organs In some cases
the difficulty in specimen interpretation by
pathologist hampers the diagnosis. Histology
could provide easier interpretation. The EUS
Unit was involved in a European Group (Pro
Core) to study new histology needles. In 2013
the European Group has expanded to an International Group and the ASPRO Study is the first
DIVISION OF MOLECULAR ONCOLOGY
step of this International cooperation on this
field.
• CAPS International. International Program on
Pancreatic Cancer Screening (John Hopkins
Baltimore Principal Investigator).
There is nowadays a great interest in the definition
of the characters that could lead to an early diagnosis of Pancreatic Adenocarcinoma and the def-
inition of screening modalities on high risk populations is very important. In 2011 our Group has
participated to the 1st International Meeting on
Pancreatic Cancer Screening, a consensus paper published in 2013. After that the CAPS Group
established an international screening of high risk
patients.
Paolo Giorgio Arcidiacono
Gastrointestinal surgical oncology Unit
Consistently at the forefront of surgical innovation,
the Gastrointestinal and Peritoneal surface Surgery Unit is transforming the multidimensional field
of surgery through delivering compassionate clinical care, making groundbreaking discoveries and
training future surgeons. From basic science to
clinical investigations, the Unit is working in a wide
range of research that is transforming the field of
surgery. The Section of Gastrointestinal and Peritoneal Surface Surgery has maintained its prominence as a national and international leader in the
surgical management of patients with complex
diseases by building on its rich heritage while
continuously evolving to define today’s and tomorrow’s standards of care. In 2013, the Unit expanded its faculty in critical areas of colorectal
and upper GI surgical oncology, and peritoneal
surface malignancy with wide use of minimally invasive techniques exploring new surgical approaches to a variety of difficult clinical problems.
The Unit maintains a national and regional presence in clinical trials that aim at improving treatment for patients with esophageal, gastric, colorectal and peritoneal surface malignancy. Over
the past years the Unit has pursued the following
projects:
1. Role of induction of innate immunity in nonmetastatic rectal cancer after neo-adjuvant radio-chemotherapy and its relationship with patient survival and pathological response.
2. Tumor regression grade after neo-adjuvant
chemotherapy plus surgery in Upper GI malignancy.
3. HER-2 expression after neo-adjuvant
chemotherapy for Upper GI malignancy.
4. Single- site surgery application in staging laparoscopy in order to reduce the rate of port
metastasis.
5. Application of a novel surgical technique (APPEAR) in the treatment of rectal cancer.
6. Sentinel node mapping in Upper GI Cancer.
7. Clinical application of cyto-reductive surgery
and HIPEC (intra peritoneal chemotherapy) in
the treatment of peritoneal carcinomatosis in
Upper GI and colorectal cancer.
8. Role of radio chemotherapy in the esophagealgastric junction (EGJ) tumors.
Gianfranco Ferla
Head and neck oncology Unit
During 2013 our research activity focused on the
following areas:
• Patient recovery after surgery, with the implementation of an Enhanced recovery after surgery (ERAS) program in order to reduce morbidity, improve recovery, and shorten hospital stays
of surgical patients. In our Unit this program has
been applied in patients undergoing major oncologic surgical procedures.
• New technologies for early diagnosis of head
and neck cancer. In 2013, we used Narrow
Band Imaging (NBI) technology in the evaluation
of precancerous laryngeal and oropharyngeal
lesions. We gathered preliminary data on the reliability of this technology that will undergo fur-
ther investigation during patient follow up over
the following years.
• HPV detection in oral and oropharyngeal cancer. We aimed at replicating the findings of previous studies on detection of HPV DNA in lymph
node FNABs in head and neck cancer of unknown origin (CUP-syndrome) patients.
• Biomarkers associated with relapse of Chronic
Rhinosinusitis with Nasal Polyps (CRSwNP). In
collaboration with the Immunology and Allergology department, we investigated the role of
Long Pentraxin 3 (PTX3) as a possible relapse
biomarker in CRSwNP after surgical treatment.
Our results show that PTX3 is a promising biomarker that could be implemented for use in
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Clinical Research Units
clinical settings to guide therapeutic decision.
• New technologies for diagnosis of Granulomatosis with Polyangiitis (GPA, Wegener’s). We
conducted a pilot investigation on the possible
role of NBI technology in the recognition of submucosal vascular patterns possibly associated
with GPA. We identified and classified some
mucosal vascular pattern visible with NBI light in
GPA patients and we evaluated their diagnostic
potential.
• Multicenter study concerning the head and
neck manifestations of GPA.
• Prediction of outcomes in aesthetic surgery with
the development of a mathematical model to
assess adherence of pre-rhinoplasty projects
with surgical results.
• Mini invasive new surgical approaches to parapharyngeal space.
Mario Bussi
Multidisciplinary group for thoracic surgical oncology
New Positron Emission Tomography-derived parameters as predictive factors for recurrence in resected Stage I non-small cell lung cancer (Giulio
Melloni)
The recurrence rate for stage I non-small cell lung
cancer is high with 20-40% of patients that relapse after surgery. We evaluated new F-18 fluorodeoxyglucose positron emission tomography
derived parameters, such as standardized uptake
value index, metabolic tumor volume and total lesion glycolysis as predictive factors for recurrence
in resected stage I non-small cell lung cancer.
Solitary fibrous tumors of the pleura: himmunohistochemical analysis and evaluation of prognostic
factors after surgical treatment (Alessandro
Bandiera)
Solitary fibrous tumors of the pleura (SFTP) are
rare neoplasms with unusual histological and clinical features. Although surgery is the treatment of
choice tumor recurrence may occur after complete resection. The aim of the study was to identify the clinical and pathological features of SFTP
associated with a higher risk of recurrence after
surgical treatment.
Results of surgical treatment of large cell and
large cell neuroendocrine carcinomas of the lung:
a clinico-pathological study (Angelo Carretta)
Large cell neuroendocrine carcinomas (LCNEC)
of the lung are a group of tumors with peculiar
histological and clinical features. Aim of the study
is to analyze the results of surgical treatment of
LCNEC and to assess the prognostic role of clinical and histological factors.
Pediatric parapneumonic empyema: a correlation
between preoperative chest ultrasonography and
surgical evidence (Paola Ciriaco)
The purpose of this study was to evaluate the role
of chest ultrasonography in staging pediatric
parapneumonic empyema in terms of a correlation between ultrasound patterns and surgical evidence.
Dumbbell mediastinal neurogenic tumors: diagnostic and surgical strategy (Giampiero Negri)
Neurogenic mediastinal tumors presents an intraspinal extension in 10% of the cases and rarely
an intramediastinal development, becoming the
so called Dumbbell neurogenic tumor (DNT). Aim
of the study was to analyze diagnostic and surgical strategy of the mediastinal DNT in terms of
surgical approach end long term results.
Piero Zannini
DIVISION OF MOLECULAR ONCOLOGY
Oncogenesis in liver neoplasms Unit
The Hepatobiliary Unit is a multidisciplinary clinical
unit where the traditional gap between physicians
and surgeons has been overcome to reach the
optimal standards of patient care. Indeed, the
medical staff includes hepatologists and hepatobiliary surgeons who share their specific competences to treat in an unique environment both
“medical” and “surgical” patients.
Clinical activities are mainly focused on hepatobiliary tumors and chronic liver diseases, including
primary (hepatocellular carcinoma and cholangiocarcinoma) and metastastic liver tumors (mainly
liver metastases from colorectal cancer), liver cirrhosis and related complications (portal hypertension, ascites, esophageal varices), benign and
malignant diseases of the biliary tract, acute and
chronic hepatitis.
As far as liver tumors are concerned, the research
activities are mainly focused on the outcome (in
term of overall survival and disease-free survival)
of patients affected by liver metastases from colorectal cancer and treated by surgery and adjuvant/neo adjuvant chemotherapy. Studies regarding the prognostic factors of survival after surgery
and the impact of locoregional chemotherapy on
the outcome after surgery have been published
(World J Surg, Ann Surg Oncol, J Gastroint Surg,
J HBS). Among the speculative studies about the
liver metastases from colorectal cancer, the hepatobiliary unit have been involved in cooperative
protocols of study with the Unit of Immunobiotherapy of Melanoma and Solid Tumors. Surgical
specimens have been collected after liver resection for colorectal liver metastases to characterize
the expression of OX40 and 4-1BB on peripheral
blood lymphocytes and in tumor and lymphoid tissue of oncological patients. The study has ended
the phase of case collection and it is still ongoing
for the final analysis of the results.
During 2013, further attention has been focused
on hilar cholangiocarcinoma: indeed, patients affected by this kind of neoplasm still have a severe
long term outcome despite surgical treatment,
which presently represents the only potentially
curative treatment. In this setting, studies regarding oncogenesis may contribute to amelioration of
overall and disease free survival of these patients.
Gianfranco Ferla
Pancreatic cancer Unit: biology
and new therapeutic approaches
Pancreatic cancer is the fourth cause of cancer
mortality in the Western world and it has the worst
prognosis among malignancies, with a 5-years
survival around 5%. The San Raffaele Hospital is
one of the leading Italian Institutes for the treatment of pancreatic cancer and our Unit is devoted to the identification of new therapeutic approaches against this devastating disease. One
of the mainstay to improve the results of surgery
is chemotherapy (CT). Jointly with the Medical
Oncology Unit, we are currently evaluating the efficacy of different adjuvant CT schemes in resectable pancreatic cancer, including preoperative (neoadjuvant) CT. The San Raffaele Hospital is
the Italian leading centre in patients enrollment in
an ongoing multicentre, randomized, phase II-III
study about perioperative CT. In this setting, we
recently demonstrated, through a case-match
study, the safety of neoadjuvant approach in the
short-term postoperative outcome of pancreatic
resections. In patients with locally advanced pancreatic cancer we are evaluating further ap-
proaches such as radiation therapy and cryothermal ablation. A phase I study has been completed to determine the maximum tolerated radiation
dose of an integrated boost to the tumour subvolume infiltrating vessels, delivered simultaneously
with radical dose to the whole tumour. Cryothermal ablation of the tumour can be applied under
Endoscopic Ultrasound guidance to reduce the
tumour mass, potentially increasing the resection
rate of locally advanced cancer and patient survival. We are collaborating with the Endosonography Unit to develop a prospective randomized
study on this matter. Further, in collaboration with
the Tumor Immunology Unit, we are investigating
the role of tumor immune infiltrates in pancreatic
cancer regression or promotion. Finally, we have
evaluated the oncologic safety of islet autotransplantation (IAT) in the liver of patients with pancreatic and periampullary malignancy. We applied IAT
in 17 patients with malignancy, and none of them
developed metastases in the transplantation site.
Gianpaolo Balzano
23
DIVISION OF MOLECULAR ONCOLOGY
Clinical Research Units
Pathology Unit
Our research activity is mainly focused on three
major topics: hematopathology, pancreatic neoplasms and urologic malignancies.
In particular, during 2013, our hematopathology
group has been actively involved in two major
fields, the link between infectious agents, mainly
bacteria, and lymphoproliferative disorders and
the relation between neoplastic cells and microenvironment in lymphomas. In the latter area,
our investigation involves the relationship between
neoplastic cells and microenvironment in hematologic neoplasms, including indolent forms (such
as marginal zone lymphomas, chronic lymphocytic leukemia, follicular lymphomas, plasma cell
dyscrasias, chronic myeloproliferative disordes
and myelodysplastic syndromes) and aggressive
hemopathies. In this context several studies are
currently active and in particular the role of accessory cells - T lymphocytes subclasses, monocyte-macrophages cells, dendritic and stromal
cells - in these heterogeneous malignancies. Regarding T lymphocytes, we are currently characterizing their immunomodulatory role in follicular
lymphomas and a cooperative study with Prof. C.
Vinuesa (Immunological Institute, Australian National University, Canberra, Australia) for the characterization of the neuroendocrine features of T
follicular helper cells, is in progress.
In addition, we recently investigated the morphology and the immunophenotypic and molecular
features of Erdheim-Chester disease. This is a
rare, progressive and fatal disease of monocytes/macrophages cells, involving bone marrow
and several other tissues and organs. In this disease monocytes/macrophages are mutated in
Braf and display unique phenotypic and functional
properties. We have also identified the presence
of mutated monocytes not only in involved organs, but also in the peripheral blood, paving the
way for a new diagnostic approach in this disease.
We have performed, in cooperation with the
COMP of the Dana Farber Cancer Institute in
Boston, a massive sequence analysis of a series
of neuroendocrine pancreatic neoplasms with the
identification of a number of putative relevant
gene alterations.
Furthermore, the scientific activity of the Pathology
unit relies also on the collaboration with Research
Groups at our institution, but also with National,
European and Intercontinental leading Institutions,
where some of our staff members act as chairmen and coordinators of international studies.
The scientific production from Our Unit is sound
and mostly devoted on the translational implications of basic discoveries, as witnessed by the
several high-quality publications present within
top scientific journals with high Impact Factor.
Beside the research carried on patients, Our Unit
incorporates the Mouse Histopathology Unit, with
the aim of supporting research groups in the advancement of scientific projects, by providing morphological expertise and immunophenotypic
analysis. In particular, part of these skills contributed to the development of the HSR-TIGET Test
Facility, thus enabling to obtain the certification of
compliance with the Principles of Good Laboratory
Practice (GLP) for preclinical toxicity/tumorigenicity
studies of gene therapy medicinal products.
Claudio Doglioni
Clinical lymphoid malignancies
The approach of the Clinical Unit of lymphoid malignancies against the
primary CNS lymphomas
Ten years ago, we established a multidisciplinary
scientific group focused on primary CNS lymphomas (PCNSL), the International PCNSL Collaborative Group (IPCG). Since then, over 100 researchers and clinicians working on PCNSL from
19 countries have been actively involved in this
group established under the sponsorship of the
International Extranodal Lymphoma Study Group
with conference grant support from the NCI, USA.
Since 2003, this multidisciplinary group has met
annually or biannually, in Europe or the USA and
meetings have been focused on multiple topics
relevant for PCNSL including neuropsychological
assessment, new targets and drugs, neuroimaging, the role of HDC/ASCT and many other important topics. The continuous updates, exchange of
ideas and debates among IPCG members has
resulted in the design and execution of key studies in this field. Debates on new concepts and
clinical trials have been the fertile background for
relevant biological and clinical studies on a challenging malignancy that straddles the border between hematology and neuro-oncology. In fact,
the IPCG has become the primary scientific group
DIVISION OF MOLECULAR ONCOLOGY
focused on improving molecular, diagnostic and
therapeutic knowledge and outcomes in PCNSL.
IPCG members have written consensus diagnostic and therapeutic guidelines and have standardized baseline evaluation and response criteria as
well as neurocognitive assessment recommendations. They have chaired several international
studies that contributed to improve the knowledge on PCNSL T-cell, intraocular lymphoma,
PCNSL in children and adolescents, and many
others. Although it is quite challenging to obtain
research funding for investigator-driven clinical research on orphan malignancies like PCNSL, cooperation within the IPCG has ushered in the era
of randomized trials in this subtype of lymphoma.
In fact, IPCG members have chaired the first two
most successfully executed randomized trials in
PCNSL, and are coordinating five ongoing randomized trials aimed to improve therapeutic efficacy and minimize neurotoxicity in the PCNSL
population.
In the next decade, the primary objectives of
IPCG collaboration are to increase the proportion
of PCNSL patients cured of their disease and to
preserve long-term neurocognitive function in PCNSL survivors.
Andrés José Marìa Ferreri
Gynecologic oncology
A retrospective multi-institutional review of patients with granulosa cell tumors (GCTs) of the
ovary treated or referred to MITO centres was
conducted. Surgical outcome, intraoperative and
pathological findings and follow-up data were analyzed. Kaplan-Meier and Cox proportional hazards analyses were used to determine the predictors for survival and recurrence.A total of 97 patients with primary GCT of the ovary were identified. The median follow-up period was 88 months
(range 6-498). Of these, 33 patients had at least
one episode of disease recurrence, with a median time to recurrence of 53 months (range 9332). Also, 47% of recurrences occurred after 5
years from initial diagnosis. At multivariate analysis, age and stage were independent poor prognostic indicators for survival; surgical treatment
outside MITO centres and incomplete surgical
staging retained significant predictive value for recurrence in both univariate and multivariate analyses.This study confirms the favorable prognosis
of GCTs of the ovary, with 5-year overall survival
approaching 97%. Nevertheless, prognosis after
20 years was significantly poorer, with 20-year
survival rate of 66.8% and a global mortality of 30-
35. These findings support the need for lifelong
follow-up even in early-stage GCT.
Treatment with anticancer agents induces dysregulation of specific Wnt signaling pathways in human ovarian luteinized granulosa cells in vitro.
Chemotherapy has been associated with premature ovarian failure and infertility in women with
cancer. It is well known that anticancer drugs reduce the primordial follicle pool and harm the
ovarian blood vascularization leading to ovarian
atrophy. However, their mechanism of injury still
remains unclear.
Treatment with doxorubicin (DXR), paclitaxel (PC),
and cisplatin (CP) affected LGCs viability by inducing apoptosis and downregulating both estrogen receptor β and follicle-stimulating hormone
receptor in a dose-dependent manner. Several
members of the WNT signaling pathway are expressed in granulosa cells where they regulate
follicle development, ovulation, and luteinization.
Here we show that treatment with DXR, PC, and
CP induced upregulation of WNT4 expression,
whereas WNT3 expression was downregulated
by DXR and PC and upregulated by CP.
Giorgia Mangili
25
DIVISION OF MOLECULAR ONCOLOGY
Clinical Research Units
Medical oncology Unit - Clinical trials
The Unit is committed to design and conduct investigator-driven clinical trials, is involved in new
drugs development and cooperate with teams of
laboratory researchers to identify molecular prognostic or predictive biomarkers in the therapeutic
management of gastro-intestinal and central nervous system (CNS) cancer.
Ongoing projects can be listed under four main
topics:
1. Pancreatic cancer: a) definition of molecular
prognostic/predictive tools on markers generated by assays of gene expression and single
nucleotide polymorphisms involved; b) analysis
of the role of inflammation as prognostic/predictive variable; c) development of new therapies and therapeutic strategies, including the
role of adjuvant and neoadjuvant polichemotherapy in stage I-II disease; of taxanes and
metformin in stage III and IV disease; of maintenance therapy in stage IV disease as well as of
salvage therapies in patients with progressive
disease.
2. Biliary tract cancer: assessment of new drug
combinations in upfront and second-line therapeutic management of patients with metastatic
disease and of the role of K-Ras mutations in
predicting the activity of anti-EGFR agents.
3. Colo-rectal cancer: evaluation of the feasibility
of an adaptive strategy in preoperative radiochemotherapy for rectal cancer and development of new combination therapies in
metastatic colon cancer.
4. CNS tumors: assessment of a) the role of target therapies in meningiomas; b) the combination treatment for elderly patients with glioblastoma multiforme; c) the concomitant and sequential chemoradiation in grade III gliomas.
Michele Reni
Medical oncology Unit - Phase I and lung cancer clinical trials
The research objective is to improve patients outcome by applying personalized therapies. The activities of the group are divided into two main areas: clinical trials and translational studies (molecular targets, systemic response against tumor and
tumor mico-environment).
There are 20 ongoing clinical trials (n) focusing on
following targets: EGFR pathway and resistant
mechanism (3), K-ras (1), ALK (4), FGFR (1), B-raf
(2), immunotherapy (anti PD-L1 target, 4), genotype guided therapies (ITACA and EPIC study),
NGR-hTNFα in mesothelioma (2) and palliative radiotherapy + pan-histonedeacetylase (1).
We developed a serum multivariate protein-based
test, VeriStrat, that classifies NSCLC patients into
2 VeriStrat categories Good and Poor, according
to the overall survival with EGFR-TKIs. The predictive value of the test was prospectively evaluated
in the independent multi-center trial: PROSE. This
is the first prospective biomarker-stratified study in
thoracic oncology to test treatment/biomarker interaction. NSCLC patients previously treated platinum based chemotherapy were randomized between erlotinib or chemotherapy (pemetrexed or
docetaxel). The trial reached its primary objective
of showing significant interaction between VeriStrat classification and therapy. The results showed
(ASCO oral presentation) that VeriStrat poor classified patients had shorter survival on erlotinib
compared with chemotherapy (3 vs 6.4 months,
respectively); HR 1.72 (95% CI 1.08-2.74), p
0.021, while no difference was observed in VeriStrat good classified patients (11 vs 11 months, respectively); HR 1.06 (95% CI 0.77-1.46), p
0.714. The study also confirmed a strong prognostic value of the test. EGFR and KRAS mutation
analyses were also performed that confirmed independent predictive value of the proteomic test.
A longitudinal analysis shoved that 34% baseline
VeriStrat good patients treated with erlotinib who
changed to poor had worse PFS compared with
those whose remained good. In conclusion, our
studies indicate that VeriStrat test can guide treatment decision making in NSCLC patients with unknown or wild type EGFR status in 2nd line setting. The possible clinical impact of changes in
VeriStrat classification during therapy requires further investigation.
Vanesa Gregorc
DIVISION OF MOLECULAR ONCOLOGY
Onco-hematology
The San Raffaele Onco-Hematology Group participates to several original, national and international clinical and traslational studies, at our Institute and within disease networks (NILG, GIMEMA,
EORTC, EBMT). During 2013 we continued to
enroll patients with AML, ALL, MM, MDS and
MPN in local and multicentric phase II/III trials
aimed at evaluating the efficacy of new drugs
and/or new treatment strategies. We also partecipated to several cooperative studies within the regional hematologic network (REL), for the diagnosis and treatment of acute leukemias, MDS, CML
and MM. Within the REL, we contributed to implement the MDS web-based registry which is collecting multiple epidemiologic, clinical, biological
and genetic data from MDS patients followed at
the regional haematologic centers. This registry
already includes hundreds of patients and keeps
on enrolling new patients every year, being periodically updated on their clinical and therapeutic
outcomes. In parallel, the network of local biological banks, which has been set up in 2012, has
provided cells/nucleic acids from MDS patients
for the first biological studies approved and started up within the REL. Data from the registry and
the biological samples are always available to participating centers for ongoing and future biological
studies. The OSR AML bio-bank was further developed in 2013 providing samples for molecular
characterization with new generation assays. This
bio-bank also provides samples to several laboratories in San Raffaele-DIBIT thus supporting several important pre-clinical studies in the field of
AML and gene therapy. Our group went on in
2013 with studies on metabolomic and angiopoiesis of MGUS and multiple myeloma and in
studies on WT1 monitoring to predict MRD persistence or recurrence after allogeneic transplantation and evaluating WT1 levels, as a quantitative
marker of leukemic contamination, in autologous
PBSC used for autotransplant after myeloablative
chemotherapy. A paper reporting the results of
this last study is in preparation and will be submitted in early 2014. Our Group has also particularly
focused and distinguished in the curative treatment of elderly patients (older than 65-70 yrs) with
AML and MDS, utilizing adapted strategies, including autologous or allogeneic transplantation.
Massimo Bernardi
27
DIVISION OF MOLECULAR ONCOLOGY
Introduction by the Director
URI
Urological Research Institute
URI’s mission is to develop translational projects in clinically relevant topics of uro-oncology and functional urology. In order to effectively develop a translational research program, i.e. to create a close relationship between preclinical researchers and the physicians and surgeons who are faced with patients’
needs and expectations on a daily basis, URI has been structured into Disease Units. Five different disease units currently make up URI. Among these, the Prostate Cancer Unit is devoted to translationally investigating prostate cancer, from bench to bedside, having the unique opportunity to use clinical data from
one of largest and most comprehensive patient datasets in Europe. Likewise, the Bladder Cancer Unit is
mainly devoted to investigating transitional cell carcinomas of the bladder, along with cancer of the upper
urinary tract system. In this specific context, URI provides the unique opportunity to study these issues
from multiple approaches, from in-vitro models of tumour cells to large patients datasets, including both
data from non-muscle invasive and muscle-invasive bladder cancers. Third, the Kidney Cancer Unit provides excellent research opportunities in terms of projects on renal cell carcinoma, with one of the largest
single-institutional datasets in the world. These 3 datasets have been rigorously organized in a web-based
system which also provides a user-friendly and private way for patients to update their prospective followup themselves. Moreover, URI has a robust experience in the field of Functional Urology, which includes
the translational study of the pathology of the lower urinary tract, the kidney and the ureter. In this specific
context, URI has been involved in many multinational preclinical research projects, which have also been
translated into close relationships with pharma-companies, thus enabling the development of potentially
novel molecules and the corroboration of existing drugs. Lastly, URI has a solid Sexual Medicine Unit
which is mainly devoted to the translational study of male sexual and reproductive health, with a clear vision of the real-life setting and the transfer of preclinical know-how into daily management of issues relating to the desire for parenthood, sexual health as a proxy of general male health and overall quality of
life.
As a whole, these five Disease Units have achieved an impressive number of research goals, with collaborations across the world, and numerous publications in peer-reviewed indexed journals. This is made
possible thanks to the structural organization of the units themselves. Indeed, under the guidance of the
various heads of units, each group has provided research and educational opportunities for Medical students, residents in training and research and clinical fellows.
DIVISION OF MOLECULAR ONCOLOGY
Research Units, URI
Urological pre-clinical research Unit
The URI preclinical research unit encompasses
translational research modalities in clinically relevant topics of functional urology and uro-oncology.
During 2013, we have implemented several research projects addressing for instance the issue
of erectile dysfunction after radical prostatectomy,
innovative therapeutic approaches to treat lower
urinary tract symptoms and surgery-induced neuropraxia, novel potential targets for the treatment of
bladder cancer as well as studies on markers of
prognostic and therapeutic relevance in prostate
cancer. To facilitate the translational interaction between clinicians and basic scientists we are investing resources in the collection of biological
materials obtained from informed patients, which
will be preserved in a dedicated biobank, and implemented several Disease Units that will comprehensively address research projects on prostate,
bladder, and renal cancer as well as on functional
urology and sexual medicine. A particularly relevant
project that succeeded in 2013 is the investigational study on a novel treatment in Peyronie’s disease (PD). PD is a connective tissue disorder of
the tunica albuginea (TA). Currently, no gold standard has been developed for the treatment of the
disease in its active phase. We have assessed the
effects of a local injection of adipose tissue-derived
stem cells (ADSCs) in the active phase of a rat
model of PD on the subsequent development of
fibrosis and elastosis of the TA and underlying
erectile tissue. This study is the first to test stem
cell therapy in an animal model of PD. Injection of
ADSCs into the TA during the active phase of PD
prevents the formation of fibrosis and elastosis in
the TA and corpus cavernosum.
Petter Hedlund
Functional urology
Urological dysfunctions and lower urinary tract
symptoms still represent a major problem in the
management of genitourinary organs pathologies.
Goal of the Unit is to study the patho-physiology
as well as to identify novel therapeutic opportunities
for the overactive bladder (OAB), prostatic and
ureter disorders and improving functional recovery
after urological cancer surgery by means of experimental modelling. In 2013, we have demonstrated
that the α1-adrenoceptor antagonist silodosin has
excellent functional selectivity both in vivo to relieve
pressure-load of the rat obstructed ureter and exvivo to inhibit contractions of human isolated
ureters, suggesting that this medical expulsive therapy may also facilitate ureter stone passage in humans. Furthermore, we have confirmed the role of
the endocannabinoid system in controlling the urinary functions; indeed chronic treatment with the
cannabinoid degrading enzyme fatty acid amide
hydrolase (FAAH) inhibitor oleoyl ethyl amide (OEtA)
alters sensory urodynamic parameters and reduces experimental bladder overactivity. The presence of FAAH and cannabinoid receptors (CB) in
the bladder and activation of CB-associated intra-
cellular signals after intravesical OEtA in turn suggest a local role for FAAH in micturition control,
even if OEtA might also act on central sensory
pathways to contribute to these effects. Along this,
we have assessed whether spinal inhibition of
FAAH would have urodynamic effects both in normal rat and rats with experimental OAB induced by
partial urethral obstruction or prostaglandin E2.
After quantification of FAAH and CB1 and CB2 receptors levels in the sacral spinal cord, we have
shown that FAAH blockade in the sacral spinal
cord resulted in urodynamic effects in normal rats
and diseased rats. Thus, the spinal endocannabinoid system may be involved in normal micturition
control and it appears altered in OAB. Finally, we
have started several corporate collaborations to investigate the role of TRPM8 receptor in modulating
urinary functions upon the presence of LUTS, to
evaluate the effects of s.repens extracts in the experimental BPH, and to assess the effects of the
bladder GAG layer replenishment in experimental
cystitis occurring after chemical and surgical mucosal damages.
Fabio Benigni
29
DIVISION OF MOLECULAR ONCOLOGY
Clinical Research Units, URI
Prostate cancer
Pre-clinical research: We have started a novel research project addressing the use of human decellularized tissue specimens to identify molecular
markers associated with metastatic events in PCa
patients. Unmasking which primary tumors harbor
cells with an aggressive phenotype may improve
prediction of metastasis. We have purified human
prostate-derived ECM preserving the stromal-derived (glyco)-protein scaffold and observed that
pathological ECMs are differently infiltrated by PCa
cells in a way strictly dependent on the inherent
cancer cell invasive potential. We are exploiting this
methodology to unveil the metastatic phenotype in
organ-confined, low grade tumors.
Clinical research: We have investigated the impact
of the stage migration phenomenon on the risk of
lymph node invasion in patients over the last 20
years. Our analyses shows that patients with intermediate- and high-risk PCa still harbor significant
risk of lymph node invasion at final pathology. Thus,
extended lymph node dissection should not be
omitted in these individuals. Additionally, we tested
the accuracy of currently available risk stratification
tools to predict the risk of lymph node invasion.
We also studied the impact of adjuvant radiotherapy on cancer-specific mortality according to PCa
features and developed a novel risk score based
on pathological Gleason, pathological stage, and
lymph node invasion to determine the ideal candidates for adjuvant radiotherapy following radical
prostatectomy. This novel prognostic tool will help
clinicians better counsel their patients, plan followup protocols, and select candidates for multimodal
treatments. We also identified the predictors of
cancer-specific survival in patients who experience
biochemical recurrence after adjuvant radiotherapy.
Our analyses showed that not all patients who
recur after adjuvant radiotherapy die from PCa.
However, patients with more aggressive disease
are at higher risk of experiencing cancer-specific
mortality and, thus, may benefit from additional
secondary therapies.
Finally, we focused on quality of life and functional
outcomes after radical prostatectomy and evaluated the impact of robotic approaches on the
probability of recovering urinary continence and
erectile dysfunction after surgery.
Alberto Briganti
Bladder cancer Unit
The Uro-Oncology Unit for urothelial neoplasms
handles the diagnosis, treatment and follow-up of
bladder cancer (BC) and upper urinary tract tumors. Performing nearly 350 endoscopic resections and more than 120 radical cystectomies per
year, it is one of the highest volume surgical oncology units world-wide.
• Diagnostics: We use exclusively flexible, highdefinition tools (video endoscopy and cystoscopy in HD) and routinely use the latest diagnostic methods including early biological diagnosis by F.I.S.H., and diagnostic techniques using PDD (Photodynamic Diagnosis) or NBI (Narrow Band Imaging). The diagnostic techniques
for muscle-invasive BC include the latest imaging tools (MRI, CT/PET) that allow for reliable
clinical staging.
• Therapeutics: For non-muscle invasive BC Synergo® technology is now available for local
chemo-hyperthermia (RITE) and ablative treatment with a Holmium laser for small neoplasms.
For local muscle-invasive BC, many new techniques of post-cystectomy bladder reconstruction have recently been developed to spare the
nerves responsible for sexual potency, particularly complex surgical procedures suitable pri-
marily for young subjects with organ-confined
disease. Our unit was among the first to perform
robot-assisted laparoscopic radical cystectomies, gaining considerable experience also in
the reconstructive phase.
• Scientific Activities: No information is currently
available on the molecular events resulting from
cannabinoid receptor (CB) activation in urothelial
cancer. We investigated the expression of CBs
in primary human bladder carcinoma, quantified
the anti-proliferative, ceramide-mediated activity
of CB2 agonists in BC cell lines, and provided
insight to the mechanisms of action of glycoshingolipids-mediated effects induced by
CB2 agonists. The data support the use of CB2
agonists to treat BC and possibly limit disease
progression. Our intense clinical research is evidenced by the numerous publications and
communications at International Conferences.
The Unit has also established close collaborations with prestigious European and American
Urological centers, providing a fruitful exchange
of expertise and enabling many young residents
to acquire valuable experience in renowned
centers of Urological excellence.
Renzo Colombo
DIVISION OF MOLECULAR ONCOLOGY
Renal cancer Unit
When to perform lymph node dissection in patients with renal cell carcinoma:
a novel approach to the preoperative assessment of risk of lymph node
invasion at surgery and of lymph node progression during follow-up
The question of whether to perform lymph node
dissection (LND) in RCC is still under debate. Indeed, although level one evidence showed no
benefit in performing LND at the time of nephrectomy, several retrospective reports seem to suggest that those results should be applied to lowrisk cases only. A population-based analysis recently showed that there has been a persistent
decline in the use of LND at radical nephrectomy
over the last decade. In this context, it appears
crucial to identify which patients may benefit from
LND at the time of nephrectomy, but to date only
two predictive models have been proposed to accurately identify patients at risk of lymph node invasion (LNI). Unfortunately, those reports were not
able to address the major limitation of a nonquantifiable rate of false-negative LNI cases owing
to their inclusion of patients treated with limited
LND and the exclusion of patients who did not
undergo LND.
By relying on a unique approach, combining the
risk of harbouring LNI and/or LN progression during the follow-up period, we provided the first clinical presurgery statistical model predicting the
need for LND in RCC setting. The model showed
excellent accuracy and calibration with a significant benefit in decision curve analyses. Those
performance characteristics are remarkable given
the fact that no pathological variables, which traditionally show a higher accuracy, were used. For all
those reasons, our model can be considered the
first attempt to identify before surgery, based exclusively on clinical variables, those cases in
which the tumor shows a LN trophism during their
natural history and that might benefit from a LND
at the time of surgery.
Roberto Bertini
Sexual medicine Unit
• Pre-clinical research: The exact role of the endocannabinoid-regulatory enzyme fatty acid
amide hydrolase (FAAH), expressed in the human and rat ejaculatory system, is yet unknown.
We investigated the effect of an acute treatment
with a peripherally-acting FAAH inhibitor
(URB937) by measuring the ejaculatory latencies and intraspongiosus suprasystolic pressures after apomorphine-induced ejaculation reflex in vivo. The data show that pharmacological
inhibition of FAAH enzyme significantly and
dose-dependently prolongs both the latency
and inter-ejaculatory times after apomorphine,
without changing the single reflex strength.
Thus, FAAH and endocannabinoids may represent interesting drug targets for premature ejaculation.
• Clinical research: In a comprehensive investigation of the link between men’s sexual dysfunction and general health status, we found that
sexual health declines and concomitant morbidities increase with age. We also found that
the severity of ED accounts for a higher association of health significant comordities as scored
with the Charlson comorbidity index (CCI), a reliable proxy of lower general health status, regardless of the etiology of ED.
• Seeking to evaluate prevalence and predictors
of ED in young men, we found that one out of
four suffering from ED is younger than 40, with
almost half of these suffering from severe ED.
As a proxy of general male health status, these
results highlight the potential role of ED severity
as a harbinger of medical disorders in men under 40.
• In the field of reproductive medicine, we conducted a survey of opinions concerning preoperative sperm banking among Prostate Cancer
(PCa) patients prior to surgery and found that
this is relevant for one fifth of patients. Considering the incidence of PCa and prevailing attitudes
toward delayed parenthood, providing information on the risk of infertility and possible fertility
preservation interventions is critical at the time
of diagnosis.
• Finally, a deranged metabolism has been
shown to actively affect male reproductive function. Thus, we assessed prevalence of Metabolic Syndrome (MetS), correlations of MetS
with clinical characteristics, and its impact on
semen and hormonal parameters in men presenting for primary couple’s infertility.
Andrea Salonia
31
DIVISION OF MOLECULAR ONCOLOGY
Selected publications
Abdollah, F and Boorjian, S; Cozzarini, C; Suardi, N; Sun, M; Fiorino, C; Di Muzio, N;
Karakiewicz, PI; Montorsi, F; Karnes, RJ; Briganti, A. Survival following biochemical recurrence
after radical prostatectomy and adjuvant radiotherapy in patients with prostate cancer: The impact
of competing causes of mortality and patient stratification. Eur. Urol.: 2013; 64(4): 557-564 - Article
IF 2012: 10,476
Abdollah, F; Suardi, N; Cozzarini, C; Gallina, A; Capitanio, U; Bianchi, M; Sun, M; Fossati, N;
Passoni, NM; Fiorino, C; Di Muzio, N; Karakiewicz, PI; Rigatti, P; Montorsi, F; Briganti, A. Selecting the Optimal Candidate for Adjuvant Radiotherapy After Radical Prostatectomy for Prostate
Cancer: A Long-term Survival Analysis. Eur. Urol.: 2013; 63(6): 998-1008 - Article
IF 2012: 10,476
Abdollah, F; Suardi, N; Gallina, A; Bianchi, M; Tutolo, M; Passoni, N; Fossati, N; Sun, M; dell’Oglio, P; Salonia, A; Karakiewicz, PI; Rigatti, P; Montorsi, F; Briganti, A. Extended pelvic
lymph node dissection in prostate cancer: A 20-year audit in a single center. Ann. Oncol.: 2013;
24(6): 1459-1466 - Article
IF 2012: 7,384
Apollonio, B; Scielzo, C; Bertilaccio, MT; Ten Hacken, E; Scarfò, L; Ranghetti, P; Stevenson,
F; Packham, G; Ghia, P; Muzio, M and Caligaris-Cappio, F. Targeting B-cell anergy in chronic
lymphocytic leukemia. Blood: 2013; 121(19): 3879-3888 - Article
IF 2012: 9,060
Castagnaro, L; Lenti, E; Maruzzelli, S; Spinardi, L; Migliori, E; Farinello, D; Sitia, G; Harrelson,
Z; Evans, SM; Guidotti, LG; Harvey, RP; Brendolan, A. Nkx2-5+islet1+ mesenchymal precursors
generate distinct spleen stromal cell subsets and participate in restoring stromal network integrity.
Immunity: 2013; 38(4): 782-791 - Article
IF 2012: 19,795
Crippa, L; Bianco, M; Colombo, B; Gasparri, AM; Ferrero, E; Loh, YP; Curnis, F; Corti, A. A
new chromogranin A-dependent angiogenic switch activated by thrombin. Blood: 2013; 121(2):
392-402 - Article
IF 2012: 9,060
Fonte, E; Apollonio, B; Scarfò, L; Ranghetti, P; Fazi, C; Ghia, P; Caligaris-Cappio, F; Muzio,
M. In vitro sensitivity of CLL cells to fludarabine may be modulated by the stimulation of toll-like receptors. Clin. Cancer Res.: 2013; 19(2): 367-379 - Article
IF 2012: 7,837
Gianni, L; Romieu, GH; Lichinitser, M; Serrano, SV; Mansutti, M; Pivot, X; Mariani, P; Andre, F;
Chan, A; Lipatov, O; Chan, S; Wardley, A; Greil, R; Moore, N; Prot, S; Pallaud, C; Semiglazov, V.
AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and
trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J.
Clin. Oncol.: 2013; 31(14): 1719-1725 - Article
IF 2012: 18,038
Hu, S; Xu-Monette, ZY; Balasubramanyam, A; Manyam, GC; Visco, C; Tzankov, A; Liu, WM; Miranda, RN; Zhang, L; Montes-Moreno, S; Dybkær, K; Chiu, A; Orazi, A; Zu, Y; Bhagat, G;
Richards, KL; Hsi, ED; Choi, WW; Han van Krieken, J; Huang, Q; Huh, J; Ai, W; Ponzoni, M; Ferreri, AJ; Zhao, X; Winter, JN; Zhang, M; Li, L; Møller, MB; Piris, MA; Li, Y; Go, RS; Wu, L;
Medeiros, LJ; Young, KH. CD30 expression defines a novel subgroup of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. Blood: 2013; 121(14): 2715-2724 Article
IF 2012: 9,060
Raccosta, L and Fontana, R; Maggioni, D; Lanterna, C; Villablanca, EJ;Paniccia, A; Musumeci, A; Chiricozzi, E; Trincavelli, ML; Daniele, S; Martini, C; Gustafsson, J; Doglioni, C; Feo, SG;
Leiva, A; Ciampa, MG; Mauri, L; Sensi, C; Prinetti, A; Eberini, I; Mora, M; Bordignon, C; Steffensen, KR; Sonnino, S; Sozzani, S; Traversari, C and Russo, V. The oxysterol-cxcr2 axis plays a
key role in the recruitment of tumor-promoting neutrophils. J. Exp. Med.: 2013; 210(9): 1711-1728
- Article
IF 2012: 13,214
DIVISION OF MOLECULAR ONCOLOGY
Ranzani, M; Cesana, D and Bartholomae, CC; Sanvito, F; Pala, M; Benedicenti, F; Gallina, P;
Sergi Sergi, L; Merella, S; Bulfone, A; Doglioni, C; Von Kalle, C; Kim, YJ; Schmidt, M; Tonon, G;
Naldini, L; Montini, E. Lentiviral vector-based insertional mutagenesis identifies genes associated
with liver cancer. Nat. Methods: 2013; 10(2): 155-161 - Article
IF 2012: 23,565
Russo, V and Pilla, L; Lunghi, F; Crocchiolo, R; Greco, R; Ciceri, F; Maggioni, D; Fontana, R;
Mukenge, S; Rivoltini, L; Rigamonti, G; Mercuri, SR; Nicoletti, R; Del Maschio, A; Gianolli, L;
Fazio, F; Marchianò, A; Di Florio, A; Maio, M; Salomoni, M; Gallo-Stampino, C; Del Fiacco, M;
Lambiase, A; Coulie, PG; Patuzzo, R; Parmiani, G; Traversari, C; Bordignon, C; Santinami, M and
Bregni, M. Clinical and immunologic responses in melanoma patients vaccinated with MAGE-A3genetically modified lymphocytes. Int. J. Cancer: 2013; 132(11): 2557-2566 - Article
IF 2012: 6,198
ten Hacken, E and Scielzo, C; Bertilaccio, MT; Scarfò, L; Apollonio, B; Barbaglio, F; Stamatopoulos, K; Ponzoni, M; Ghia, P; Caligaris-Cappio, F. Targeting the LYN/HS1 signaling axis in
chronic lymphocytic leukemia. Blood: 2013; 121(12): 2264-2273 - Article
IF 2012: 9,060
Vardi, A; Dagklis, A; Scarfò, L; Jelinek, D; Newton, D; Bennett, F; Almeida, J; Rodriguez-Caballero, A; Allgood, S; Lanasa, M; Cortelezzi, A; Orlandi, E; Veronese, S; Montillo, M; Rawstron, A;
Shanafelt, T; Orfao, A; Stamatopoulos, K; Ghia, P. Immunogenetics shows that not all MBL are
equal: the larger the clone, the more similar to CLL. Blood: 2013; 121(22): 4521-4528 - Article
IF 2012: 9,060
Von Hoff, DD; Ervin, T; Arena, FP; Chiorean, EG; Infante, J; Moore, M; Seay, T; Tjulandin, SA; Ma,
WW; Saleh, MN; Harris, M; Reni, M; Dowden, S; Laheru, D; Bahary, N; Ramanathan, RK;
Tabernero, J; Hidalgo, M; Goldstein, D; Van Cutsem, E; Wei, X; Iglesias, J; Renschler, MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. New Engl. J. Med.:
2013; 369(18): 1691-1703 - Article
IF 2012: 51,658
Selected publications, URI
Abdollah, F; Suardi, N; Cozzarini, C; Gallina, A; Capitanio, U; Bianchi, M; Sun, M; Fossati, N;
Passoni, NM; Fiorino, C; Di Muzio, N; Karakiewicz, PI; Rigatti, P; Montorsi, F; Briganti, A. Selecting the Optimal Candidate for Adjuvant Radiotherapy After Radical Prostatectomy for Prostate
Cancer: A Long-term Survival Analysis. Eur. Urol.: 2013; 63(6): 998-1008 - Article
IF 2012: 10,476
Capitanio, U; Abdollah, F; Matloob, R; Suardi, N; Castiglione, F; Di Trapani, E; Capogrosso,
P; Gallina, A; Dell’Oglio, P; Briganti, A; Salonia, A; Montorsi, F; Bertini, R. When to perform
lymph node dissection in patients with renal cell carcinoma: a novel approach to the preoperative
assessment of risk of lymph node invasion at surgery and of lymph node progression during followup. BJU Int: 2013; 112(2): E59-E66 - Article
IF 2012: 3,046
Castiglione, F; Hedlund, P; Van der Aa, F; Bivalacqua, TJ; Rigatti, P; Van Poppel, H; Montorsi,
F; De Ridder, D; Albersen, M. Intratunical Injection of Human Adipose Tissue-derived Stem Cells
Prevents Fibrosis and Is Associated with Improved Erectile Function in a Rat Model of Peyronie’s
Disease. Eur. Urol.: 2013; 63(3): 551-660 - Article
IF 2012: 10,476
33
DIVISION OF MOLECULAR ONCOLOGY
Selected publications, URI
Salonia, A; Capogrosso, P; Castiglione, F; Russo, A; Gallina, A; Ferrari, M; Clementi, MC;
Castagna, G; Briganti, A; Cantiello, F; Damiano, R; Montorsi, F. Sperm banking is of key importance in patients with prostate cancer. Fertil. Steril.: 2013; 100(2): 367-372.e1 - Article
IF 2012: 4,174
Villa, L; Buono, R; Fossati, N; Rigatti, P; Montorsi, F; Benigni, F; Hedlund, P. Effects by silodosin on the partially obstructed rat ureter in vivo and on human and rat isolated ureters. Br. J.
Pharmacol.: 2013; 169(1): 230-238 - Article
IF 2012: 5,067
DIVISION OF MOLECULAR ONCOLOGY
Tumor biology and vascular targeting Unit
Functional genomics of cancer Unit
35
DIVISION
OF
NEUROSCIENCE
Director:
Gianvito Martino
Associate Director:
Flavia Valtorta*
Research Units
Neuropsychopharmacology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 45
HEAD OF UNIT: Flavia Valtorta*
RESEARCHER: Giovanni Piccoli*
POST-DOCTORAL FELLOWS: Serena Bellani**, Maria Maddalena Valente**
PHD STUDENTS: Maria Daniela Cirnaru, Fabrizia Guarnieri **, Francesca Pischedda
FELLOW: Marco Tramarin
TECHNICIAN: Elena Monzani
Rett syndrome research group –––––––––––––––––––––––––––––––––––––––––––––––––––––– 46
GROUP LEADER: Nicoletta Landsberger
POST-DOCTORAL FELLOWS: Francesco Bedogni, Maria Maddalena Valente
PHD STUDENTS: Clementina Cobolli Gigli, Anna Gandaglia
FELLOW: Elisa Bellini
Cell adhesion Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 46
HEAD OF UNIT: Ivan de Curtis*
POST-DOCTORAL FELLOWS: Elena Chiricozzi**, Romina Macco**, Roberta Pennucci**
PHD STUDENTS: Veronica Astro**, Sara Chiaretti, Kristyna Hanusova**
FELLOW: Anna Falco
TECHNICIAN: Diletta Tonoli
Cellular neurophysiology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 47
HEAD OF UNIT: Fabio Grohovaz*
RESEARCHERS: Franca Codazzi*, Daniele Zacchetti
POST-DOCTORAL FELLOWS: Barbara Bettegazzi, Ilaria Pelizzoni
FELLOWS: Irene Bertolini, Elisabeth Mangiameli
37
DIVISION OF NEUROSCIENCE
Research Units / Clinical Research Units
Developmental Neurogenetics Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––– 48
HEAD OF UNIT: Gian Giacomo Consalez
POST-DOCTORAL FELLOW: Grazia Iaffaldano
FELLOWS: Renato Arnese, Camilla Bosone
TECHNICIANS: Aurora Badaloni, Laura Croci
Neurobiology of learning Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 49
HEAD OF UNIT: Antonio Malgaroli*
RESEARCHERS: Carley R. Benton*, Adrian Scultoreanu*, Vincenzo Zimarino
POST-DOCTORAL FELLOWS: Mattia Ferro **, Jacopo Lamanna **, Maddalena Ripamonti**
PHD STUDENTS: Alessandro Arena, Sara Spadini **
Proteomics of iron metabolism Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––– 49
HEAD OF UNIT: Sonia Levi*
RESEARCHERS: Anna Cozzi, Paolo Santambrogio
FELLOWS: Francesca Cignarella, Michela Guaraldo**, Ida Luisa Rotundo
Stem cells and neurogenesis Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 50
HEAD OF UNIT: Vania Broccoli
PHD STUDENTS: Luca Massimino**, Federica Ungaro**
FELLOWS: Maxim Bespalov, Massimiliano Caiazzo, Ernesto Ciabatti, Gaia Colasante, Maria
Teresa Dell’Anno, Serena Giannelli, Matteo Perino, Ida Luisa Rotundo, Alessandro Sessa
Molecular genetics of mental retardation Unit –––––––––––––––––––––––––––––––––––––––– 51
(Dulbecco Telethon Institute)
GROUP LEADER: Patrizia D’Adamo*
POST-DOCTORAL FELLOWS: Maila Giannandrea, Lorenzo Morè
PHD STUDENTS: Veronica Bianchi**, Maria Lidia Mignogna**
FELLOW: Michela Masetti
Clinical Research Units
Acute brain protection, Acute postoperative pain, ––––––––––––––––––––––––––––––––––– 52
Drugs and central nervous system Unit
HEAD OF UNIT: Luigi Beretta*
PHYSICIANS: Massimo Agostoni, Maria Rosa Calvi, Assunta De Vitis, Marco Gemma,
Francesco Ruggieri
FELLOW: Massimiliano Greco**
Cognitive neuroscience Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 52
HEAD OF UNIT: Stefano F. Cappa*
RESEARCHERS: Jubin Abutalebi**, Nicola Canessa**
PHYSICIANS: Maria Cristina Giusti, Sandro Iannaccone, Alessandra Marcone, Michele Zamboni
PHD STUDENTS: Chiara Crespi**, Alessandra Dodich**
DIVISION OF NEUROSCIENCE
Clinical Research Units
Experimental neurosurgery Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 52
HEAD OF UNIT: Pietro Mortini*
PHYSICIANS: Stefania Acerno, Lina Raffaella Barzaghi, Nicola Boari, Alberto Franzin,
Marco Losa, Carlo Mandelli
PHD STUDENTS: Filippo Gagliardi**, Silvia Snider **
RESIDENTS: Michele Bailo, Jody Capitanio, Andrea Cavalli, Elena Colombo, Lucio Aniello
Mazzeo, Pietro Panni, Giorgio Spatola, Alfio Spina
Eye repair Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 53
HEAD OF UNIT: Paolo Rama
POST-DOCTORAL FELLOW: Fabio Bignami
PHD STUDENT: Louise Louro
FELLOW: Chiara Giacomini
CONSULTANTS : Oriella Ambrosio, Giulio Ferrari, Federica Ferrario, Chiara Insacco, Stanislav
Matuska, Giorgio Paganoni, Elena Scandola, Maurizia Viganò
TECHNICIAN: Anna Lorusso
Functional neuroradiology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 54
HEAD OF UNIT: Andrea Falini*
PHYSICIANS: Nicoletta Anzalone, Cristina Baldoli, Valeria Blasi, Silvia Pontesilli, Roberta Scotti,
Paolo Vezzulli
PHD STUDENT: Antonella Castellano**
RESIDENT: Claudia Godi**
TECHNICIAN: Antonella Iadanza
In vivo Human molecular and structural neuroimaging Unit ––––––––––––––––––––––––– 55
HEAD OF UNIT: Daniela Perani*
RESEARCHER: Marco Tettamanti
POST-DOCTORAL FELLOWS: Chiara Cerami**, Angela Coliva**, Pasquale Della Rosa**
PHD STUDENT: Leonardo Iaccarino
FELLOWS: Silvia Caminiti**, Danilo Spada
Neuroothology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 56
HEAD OF UNIT: Mario Bussi*
PHYSICIANS: Lucia Oriella Piccioni, Roberto Teggi
CONSULTANTS: Fabrizio Ferrario, Omar Gatti
Psychiatry and clinical neurosciences Unit ––––––––––––––––––––––––––––––––––––––––––––– 56
HEAD OF UNIT: Francesco Benedetti
Psychiatry and clinical psychobiology ––––––––––––––––––––––––––––––––––––––––––––– 56
HEAD OF UNIT: Francesco Benedetti
PHYSICIANS: Sara Angelone, Cinzia Arancio, Barbara Barbini, Laura Bellodi*, Alessandro
Bernasconi, Laura Bianchi, Marta Bosia, Stefania Cammino, Marco Catalano,
Roberto Cavallaro, Maria Cristina Cavallini, Federica Cocchi, Silvia Cocchi, Cristina
Colombo*, Sara Dallaspezia, Danilo Dotoli, Stefano Erzegovesi, Linda Franchini,
Carmelo Guglielmino, Marta Henin, Marco Locatelli, Adelio Lucca, Ernestina Politi,
Laura Sforzini, Francesca Siliprandi, Enrico Smeraldi*, Raffaella Zanardi
POST-DOCTORAL FELLOWS: Elisa Galimberti**, Sara Poletti**, Daniele Radaelli**
PHD STUDENTS: Irene Bollettini, Paola Canali, Emma Fadda, Riccardo Martoni, Roberta
Riccaboni, Cecilia Smeraldi, Benedetta Vai
39
DIVISION OF NEUROSCIENCE
Clinical Research Units
FELLOWS: Margherita Bechi, Vittoria Bottelli, Chiara Brambilla, Maria Chiara Buonocore,
Ursula Catenazzi, Daniele Cavadini, Mara Ciracì, Francesco Fresi, Chiara Gavinelli,
Stefania Ozino, Giulia Paredi, Marco Piantanida, Liana Ricci, Andrea Zanoletti
RESIDENTS: Giampiero Bottero, Silvia Brioschi, Dario Delmonte, Charlotte De Santis,
Valentina Ferrari, Clara Locatelli, Antonella Rita Mastromatteo, Angelo Notaristefano,
Marco Spangaro, Irene Vanelli
LAB MANAGERS: Cristina Lorenzi, Adele Pirovano**
Sleep medicine ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 57
CLINICAL GROUP LEADER: Luigi Ferini-Strambi*
RESEARCHERS: Vincenza Elena Castronovo, Enrico Giora *, Sara Marelli,
Alessandro Oldani, Marco Zucconi
PHD STUDENT: Andrea Galbiati **
TECHNICIANS: Massimo Antonio, Daniele Bizzozero, Elisa Dallabà, Cristina Martinelli
Clinical psychology –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 58
CLINICAL GROUP LEADER: Cesare Maffei*
RESEARCHERS: Andrea Fossati*, Mariagrazia Movalli, Laura Vanzulli, Raffaele Visintini
EXTERNAL RESIDENTS: Serena Artesani, Antonella Di Biase, Michela Adele Pozzi,
Emanuela Roder, Manuela Sanvito, Edoardo Vassallo
Motor function rehabilitation ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 59
CLINICAL GROUP LEADER: Roberto Gatti
PHYSICAL THERAPIST: Andrea Tettamanti
DIVISION OF NEUROSCIENCE
INSPE
Institute of Experimental Neurology
Director:
Giancarlo Comi*
Research Units
Experimental neurology Unit
HEAD OF UNIT: Giancarlo Comi*
Experimental neuropathology ––––––––––––––––––––––––––––––––––––––––––––––––––––––– 61
GROUP LEADER: Angelo Quattrini
POST-DOCTORAL FELLOWS: Federica Cerri, Nilo Riva
PHD STUDENT: Ignazio Diego Lopez **
FELLOW: Teuta Domi
TECHNICIAN: Giorgia Dina
Experimental neurophysiology –––––––––––––––––––––––––––––––––––––––––––––––––––––– 61
GROUP LEADER: Letizia Leocani
PHD STUDENTS: Ninfa Amato**, Valerio Castoldi**, Raffaella Chieffo **,
Francesca Spagnolo **
FELLOWS: Loris Camaleonti**, Elise Houdayer, Laura Straffi
RESIDENTS: Giovanni Di Maggio**, Mario Fichera**, Arturo Nuara**, Roberto
Santangelo**
Molecular genetics of behaviour ––––––––––––––––––––––––––––––––––––––––––––––––––– 62
GROUP LEADER: Riccardo Brambilla
PHD STUDENTS: Raffaele d’Isa**, Nicola Solari**
FELLOWS: Stefania Fasano, Ilaria Morella, Alessandro Papale
TECHNICIAN: Marzia Indrigo
Neuromuscular repair ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 62
GROUP LEADER: Stefano Carlo Previtali
PHD STUDENTS: Emanuela Porrello**, Cristina Rivellini**, Daniela Triolo**
RESIDENT: Daniele Velardo**
TECHNICIANS: Isabella Lorenzetti, Rossana Tonlorenzi
41
DIVISION OF NEUROSCIENCE
Research Units, INSPE
Neuroimmunology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 63
HEAD OF UNIT: Gianvito Martino
RESEARCHERS: Linda Chaabane, Luca Muzio
POST-DOCTORAL FELLOWS: Marco Bacigaluppi**, Erica Butti, Emanuela Colombo,
Melania Cusimano
PHD STUDENTS: Benedetta Arnò**, Roberta De Ceglia, Donatella De Feo**, Francesca
Grassivaro**, Cecilia Laterza**, Amir Malvandi**, Ramesh Menon, Chiara Rossi**
RESIDENTS: Marco Di Dario, Arianna Merlini
TECHNICIANS: Andrea Bergamaschi, Elena Brambilla, Eleonora Capitolo, Francesca Ruffini
Clinical neuroimmunology ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 64
GROUP LEADER: Roberto Furlan
PHD STUDENTS: Federico Colombo**, Livia Garzetti
RESIDENT: Dacia Dalla Libera**
FELLOW: Giacomo Casella
TECHNICIAN: Annamaria Finardi
Immunobiology of neurological disorders –––––––––––––––––––––––––––––––––––––––– 65
GROUP LEADER: Cinthia Farina
POST-DOCTORAL FELLOWS: Emanuela Colombo, Ramesh Menon
FELLOW: Marco Di Dario
Neuroimaging research Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 66
HEAD OF UNIT: Massimo Filippi*
BIOENGINEERS: Elisabetta Pagani, Paola Valsasina
POST-DOCTORAL FELLOWS: Federica Agosta, Elisa Canu
PHD STUDENTS: Martina Absinta**, Francesca Caso**, Laura Parisi**, Evelina Prudente
RESIDENTS: Giulia Longoni**, Roberta Messina**, Paolo Preziosa**, Lidia Sarro**, Edoardo
Gioele Spinelli**
FELLOWS: Pilar Maria Ferraro, Sebastiano Galantucci, Maria Elisa Morelli
TECHNICIANS: Luca Dall’Occhio, Alessandro Meani, Melissa Petrolini, Stefania Sala,
Roberto Vuotto
Neuroimaging of CNS white matter –––––––––––––––––––––––––––––––––––––––––––––––– 66
GROUP LEADER: Maria Assunta Rocca
CONSULTANT: Gianna Riccitelli
PHD STUDENT: Sara Cirillo**
TECHNICIANS: Paolo Misci, Mauro Sibilia
Human inherited neuropathies Unit (Dulbecco Telethon Institute) ––––––––––––––––– 67
HEAD OF UNIT: Alessandra Bolino
POST-DOCTORAL FELLOWS: Marta Guerrero Valero, Françoise Piguet**, Ilaria Vaccari
PHD STUDENT: Roberta Noseda**
FELLOW: Antonietta Carbone
TECHNICIANS: Valeria Alberizzi, Fiammetta Viganò
Axo-glia interactions Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 68
GROUP LEADER: Carla Taveggia, FISM
POST-DOCTORAL FELLOWS: Marta Pellegatta, Amelia Trimarco
PHD STUDENTS: Maria Grazia Forese**, Evelien Fredrickx**
TECHNICIANS: Rosa La Marca, Alessandra Lucente
DIVISION OF NEUROSCIENCE
Clinical Research Units, INSPE
Inflammatory CNS disorders Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 69
HEAD OF UNIT: Vittorio Martinelli
RESEARCHERS: Filippo Martinelli-Boneschi, Federica Esposito, Lucia Moiola,
Mariaemma Rodegher
POST-DOCTORAL FELLOWS: Ferdinando Clarelli, Elisabetta Mascia, Ana Maria Osiceanu,
Marta Radaelli, Melissa Sorosina, Andrea Zauli
PHD STUDENTS: Simona Maida**, Silvia Santoro**
RESIDENTS: Valeria Barcella**, Gloria Dalla Costa**, Laura Ferrè** , Giacomo Giacalone**,
Clara Guaschino**, Giuseppe Liberatore**, Maria Josè Messina**, Marzia Romeo**,
Francesca Sangalli**
Cerebrovascular disorders ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 69
CLINICAL GROUP LEADER: Maria Sessa
PHYSICIANS: Silvia Mammi, Antonella Poggi, Luisa Roveri
PHD STUDENTS: Marco Bacigaluppi**, Raffaella Chieffo**, Grazia Maria Nuzzaco**
(until June 2013)
RESIDENTS: Giovanni Di Maggio, Giacomo Giacalone, Sara La Gioia, Luca Peruzzotti
Jametti, Davide Strambo
Memory disorders –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 70
CLINICAL GROUP LEADER: Giuseppe Magnani
PSYCHOLOGISTS: Claudia Arcari, Alessandra Barbieri, Maria Paola Bernasconi,
Rosalinda Cardamone, Chiara Dallatomasina, Monica Falautano, Agnese Fiorino,
Francesca Possa, Elisa Riboni
RESIDENTS: Elisabetta Coppi, Laura Ferrari, Roberto Santangelo
Movements disorders ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 70
CLINICAL GROUP LEADER: Ubaldo Del Carro
PHYSICIANS: Stefano Amadio, Calogera Butera, Roberta Guerriero, Maria
Antonietta Volonté
RESIDENT: Francesca Bianchi
Neuromuscular disorders –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 71
CLINICAL GROUP LEADER: Raffaella Fazio
PHYSICIAN: Marina Scarlato
POST-DOCTORAL FELLOW: Nilo Riva
RESIDENTS: Francesca Bianchi , Daniele Velardo**
Paroxysmal events ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 71
CLINICAL GROUP LEADER: Fabio Minicucci
PHYSICIANS: Bruno Colombo, Giovanna Franca Fanelli, Paolo Marchettini
RESIDENT: Giulia Pavan
ENGINEER: Marco Cursi
TECHNICIAN: Claudia Paleari
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
43
DIVISION OF NEUROSCIENCE
Introduction by the Directors
Mission and vision - The mission of the Division of Neuroscience is to understand the inner workings of
the human brain and to find the causes of, and treatments for, neurological and psychiatric diseases, i.e.
some of humanity’s most disabling disorders. To accomplish this aim, we engage in studies on the molecular and cellular mechanisms – either in vitro or in vivo – of neural cells (both neuronal and glial cells)
dysfunction, as well as in translational and clinical research projects aimed at understanding the pathogenic mechanisms of the nervous system disorders. Our aim is to discover and/or validate novel therapeutic approaches for neurological and psychiatric disorders. Since the beginning, the fundamental
approach of the Division has been the integration of basic research with clinical applications.
Organization - The Division of Neuroscience is made up of more than 300 scientists primary or secondary affiliated to 21 basic research units and 17 clinical research groups. Given the diverse backgrounds
of the scientists affiliated to the Division, considerable effort has been dedicated to the creation of a neuroscientific community, by implementing divisional seminars and journal clubs.
Goals - Fostering translational research by implementing both basic and clinical research is the main
focus of the research activity of the Division of Neuroscience. This aim has been pursued at both the scientific and organizational levels and the followings are the achievements accomplished.
Achievements - Organizational achievements: To foster cross-fertilization between clinical and wet labs
we have continued to organize weekly meetings – named ‘Neuroclub’ – for senior and junior scientists
as well as under- and post-graduate students referring to the Division. In 2013 the Neuroclub activity has
been intense, going from progress reports to focus on diseases, PhD student’s reports, and meetings
dedicated to research programs.
Wet labs have been set up allowing physician scientists from clinical wards (Neurology, Psychiatry, Neurosurgery, Ophthalmology, Neurophysiology) affiliated to the Division to have laboratory space for preclinical research and collaborations with basic research scientists.
Scientific achievements: As outlined in the reports of the single Units, important achievements have been
obtained in areas of basic research as diverse as myelin biology, developmental and regenerative neurobiology, biomaterials for nerve regeneration, stem cells and gene delivery, in vitro and in vivo molecular
mechanisms of neurodegeneration. Scientific achievements obtained in clinical research areas have been
noteworthy as those of the basic research; the most productive areas have been human brain imaging,
genetics of psychiatric disorders, inflammatory and degenerative neurological diseases, clinical neuropsychology, eye disorders and cognitive neuroscience.
Funding: In addition to numerous grants and industrial contracts, previously set strategic alliances have
been continuing (Telethon’s program project; INSpe-MerckSerono Strategic Alliance; POMS-bioengineering) and phase I/II/III clinical trials (both spontaneous and sponsored), mainly focusing on neurological and psychiatric disorders, have been initiated and/or continued.
Training Opportunities - The Division is also actively involved in the training of graduate students, organizing Ph.D. Courses in Neuroscience, Experimental Neurology, Neurobiotechnology, Developmental Psychopathology, and taking part in the Ph.D. Course in Cellular and Molecular Biology. In addition, numerous
undergraduate students, enrolled in the Schools of Medicine, Biotechnology, Psychology or Physiotherapy, have worked in the Research Units of the Division for the preparation of their thesis. No formal training for post-doctoral fellows have been organized, but post-docs have been encouraged to participate
in the numerous institutional seminars and to national or international meetings.
DIVISION OF NEUROSCIENCE
Research Units
Neuropsychopharmacology Unit
Excitation/inhibition imbalance in epilepsy and autism spectrum disorders
The correct equilibrium between excitatory and inhibitory neuronal inputs is necessary for the normal functioning of the entire nervous system, and
a variety of neurological and psychiatric disorders
are currently thought to involve disruption of this
delicate equilibrium. Among these pathologies are
epilepsy, autism spectrum disorders, intellectual
disability. A growing number of mutations in genes
coding for proteins involved in neurotransmission
have been found in familiar cases of these
pathologies. Although the number of patients suffering from these rare conditions is limited, monogenic disorders are invaluable models for clarifying the molecular mechanisms that produce
these diseases, allowing also the development of
animal models that help in elucidating the pathogenetic role of mutations affecting neuron-specific
genes.
We have studied the synapsins, neuronal phosphoproteins involved in neurotransmitter release
and neuronal development. We and others have
recently identified an array of mutations in human
synapsin genes associated with epilepsy, autism
spectrum disorder and/or mental retardation. We
expressed synapsin mutations identified in human
in mouse hippocampal synapsin knock-out (KO)
neurons. The Q555X mutation induces higher
network excitability and firing activity, recapitulating the KO phenotype. The presence of a premature termination codon in W356X synapsin renders the transcript susceptible to nonsense-mediated mRNA decay. These data support the value
of synapsin KO mice as an experimental model
mimicking the human pathology. Neuronal networks formed in vitro from synapsin KO mice
show diffuse hyperexcitability, associated with decreased strength of inhibitory transmission and increased strength of excitatory transmission, suggesting that excitation/inhibition imbalance might
be at the basis of the synapsin KO phenotype
and possibly of the corresponding human pathology. Electroencephalographic recordings of
synapsin triple knocked-out (TKO) mice show
spontaneous and evoked epileptic discharges as
well as changes in background cortical activity. In
addition, deletion of synapsins impairs social behavior, resulting in autism-related phenotypes
which become manifest before the onset of
seizures.
Flavia Valtorta
Figure 3. Hippocampal
neurons grown in culture,
expressing GFP and
stained for the
presynaptic marker
Bassoon and the
vesicular glutamate
transporter VGLUT1.
Color-inverted image.
45
DIVISION OF NEUROSCIENCE
Research Units
Rett syndrome research group
Rett syndrome (RTT) is a devastating genetic disease mainly caused by mutations in the epigenetic
transcriptional regulator MeCP2, represents one of
the most common causes of severe mental retardation in girls worldwide. In 2007 the reversibility of
the RTT condition in mice was proved, however,
there is still no effective therapy, demonstrating the
urge of a thorough comprehension of MeCP2 neuronal role. MeCP2 binds methylated DNA thereby
affecting chromatin structure and transcription; in
mature neurons, due to its high abundance,
MeCP2 acts as a wide transcriptional modulator
controlling the expression of virtually all genes. Possibly due to this reason and to technical limitations,
so far only a few direct targets of MeCP2 action
have been discovered. Further, although several
clinical evidences suggest a role played by MeCP2
in early development, almost no studies have so
far investigated its functions during brain maturation. We have produced an exhaustive analysis of
the transcriptional defects displayed by the murine
embryonic Mecp2-null neocortex. These studies
have permitted to demonstrate the existence of an
embryonic maturation delay that persists in the
perinatal age and that we hypothesize might be re-
sponsible, at least some extent, of the neuronal
defects that typically arise during postnatal life in
RTT patients. Further, we have demonstrated that,
through bioanalytic approaches never used in RTT
before, high throughput screenings can produce
precious insights over molecular pathways affected
by MeCP2 (Bedogni, 2014; Bedogni, submitted).
In a more translational approach, in collaboration
with Dr. James Eubanks (University of Toronto,
Canada) we have started a project of gene therapy aimed at producing a novel lentivirus capable
of reproducing physiological levels of MeCP2. We
prepared (and are still preparing) several constructs to produce viruses that will be soon injected in a specific Mecp2-null mouse brain area selected for its potential rescue benefits. The expression of MeCP2, the tropism of the virus and
the potential benefits will be then tested. Promising vectors will be also tested in an AAV background.
Eventually, we are ending a project describing the
role of MeCP2 in skeletal muscle development
and homeostasis (to be submitted).
Nicoletta Landsberger
Cell adhesion Unit
Molecular networks regulating migration, invasion and neuronal development
Rac GTPases interact with networks of regulators
and effectors to regulate cell motility. Analysis of
single and double knockout (KO) mice for Rac1
(Rac1N, conditional KO of Rac1) and Rac3
(Rac3KO) has revealed a role of these proteins in
the regulation of the migration and differentiation
of GABAergic interneurons. Rac1N or Rac3KO
adult animals show differential defects in the maturation of cortical and hippocampal parvalbuminpositive (PV+) GABAergic cells. A robust phenotype is observed in Rac1N mice that develop
epilepsy and stronger cognitive defects compared to Rac3KO. The inhibitory input by PV+
basket cells on hippocampal CA1 pyramidal cells
is decreased in both single KOs, although only
Rac1N mice show a parallel strong decrease of
the GABA-producing enzyme GAD67. Moreover,
Rac1N, but not Rac3KO mice, show more perisomatic terminals by other types of interneurons
on the CA1 pyramidal cells. The morphological alterations observed in the Rac1N mice correlate
with their altered hippocampal circuitry, and may
explain their specific behavioral and cognitive
deficits. We have set up primary cultures of interneuron precursors to identify protein regulators
and effectors that mediate the effects of Rac on
the maturation of interneurons. Candidate molecules analyzed include genes mutated in developmental disorders leading to impaired cognition.
Our analysis of the molecular networks functionally linked to Rac GTPases, has led to the identification of liprin-α1, a scaffold protein regulating
the protrusive activity of migrating cells. Liprin-α1
is highly expressed in some human tumors, and
our studies in vitro have shown that this protein
positively regulates tumor cell migration and invasion, by affecting the turnover of focal adhesions
and invadopodia. By using distinct assays for invasion in vivo we are also addressing the requirement of liprin-α1 for the formation of metastases
in mice, and the mechanisms used by liprin to
regulate protrusion. In this direction we have identified a complex of adaptor proteins that is needed for liprin-promoted migration and invasion.
Ivan De Curtis
DIVISION OF NEUROSCIENCE
Figure 4. Primary culture of developing interneurons isolated from mouse embryonic MGE. Staining for GABA
(green) and for nuclei (blue, DAPI) to show the increased expression of the GABAergic phenotype in vitro (DIV,
days in vitro).
Cellular neurophysiology Unit
Physiopathological mechanisms in neuroprotection, neuroinflammation
and neurodegeneration
The work of our unit is aimed to understand the
molecular and cellular mechanisms underlying
neuroprotection, neuroinflammation and neurodegeneration. In 2013 we focused our research on
the role of astrocytes by investigating two main
aspects. We studied primary astrocytes activated
by pro-inflammatory stimuli showing that they
have the potential to buffer an excess of extracellular iron, thereby protecting neurons from iron
overload in pathological conditions (Pelizzoni et
al., 2013). We also showed that activated astrocytes acquire a phenotype characterized by a
specific gene expression pattern and a higher resistance to stressing stimuli with particular regards
to oxidative stress and iron overload (Macco et
al., 2013). Therefore, we continued the gene expression profiling of primary glial cultures activated
by various pathological stimuli, in order to identify
putative biomarkers, related to specific pathological cellular processes and aimed to become a diagnostic and prognostic tool for neuroinflammatory and neurodegenerative diseases. This activity
will be pursued within the framework of the Ivascomar project of the “Cluster Tecnologico
Nazionale Scienze della Vita” (Ministry of Re-
search).
Regarding our investigations on neurons, iPSCsderived neurons derived from patients affected by
Friedreich’s ataxia were employed to characterize
intracellular iron homeostasis and susceptibility to
different oxidative stress conditions, in order to
gain new insights in this neurodegenerative disorder. The control of intracellular iron homeostasis
was also studied in an animal model for hereditary
human neuroferritinopathy (the pathogenic L-ferritin variant 498-499InsTC). A comprehensive
study of this transgenic animal model, performed
at the biochemical, morphological and physiological level, in collaboration with S. Levi and O. Cremona, demonstrated a higher neuronal susceptibility to oxidative stress. Finally, we continued the
characterization of the phosphorylation of the
translation initiation factor eIF4B upon neuronal
activation and evaluated its possible role in the
translational control of BACE1, the neuronal βsecretase responsible for the production of the
neurotoxic amyloid-β peptides that accumulate in
the brain of Alzheimer’s disease patients.
Fabio Grohovaz
47
DIVISION OF NEUROSCIENCE
Research Units
Developmental neurogenetics Unit
A “translational” approach to the study of amyotrophic lateral sclerosis
and other neurodegenerative disorders
In 2013, our lab has started a new project in the
field of axonal biology. We study axonal protein
synthesis and its regulation, in wild type mice and
mouse models of motor neuron diseases (MNDs).
While the genetic basis of familial and sporadic
amyotrophic lateral sclerosis (ALS) is being unraveled at a fast pace, our understanding of its molecular pathogenesis remains largely incomplete.
One distinctive feature of ALS is the fact that it primarily affects long range fiber tracts, i.e. the cortico-spinal tract and the peripheral nerve. In these
pathways, the axon accounts for >99% of the corresponding neuron’s total volume, a feature that is
somewhat overlooked by many neurobiologists.
Profiling studies have revealed that both growing
and mature axons possess complex and dynamic
transcriptomes. Axonal mRNA translation is tightly
regulated and plays a role in neuronal homeostasis
affecting important biological processes, including
energy production, cytoskeletal remodeling and
retrograde transport. Recent evidence indicates
that axonal regeneration in the peripheral nervous
system is impaired in the absence of local mRNA
translation. Accordingly, many patients affected by
familial and sporadic forms of ALS carry mutations
of genes involved in RNA metabolism. Taken together, this evidence points to axonal protein synthesis as a potentially crucial factor in the
pathogenesis of MNDs. In this project, we have
generated molecular tools and in vivo/in vitro models to study compartmentalized protein synthesis
and its regulation in the axon. Thanks to fluorescent ribosomal proteins (RPs) expressed in genetically defined neurons and glial cells, we will
analyze cell-autonomous and cell-nonautonomous
contributions to the pathogenesis of MNDs. This
will be achieved through immunoprecipitation of
tagged polysomes in gray and white matter
lysates, and by RNAseq analysis of RNAs loaded
onto polysomes (the neuronal and axonal “translatome”).
Gian Giacomo Consalez
Figure 5. Confocal
images of
hippocampal
neurons transduced
with a lentivirus
encoding a green
fluorescent
ribosomal protein
(green); red, ankyrin
G, a marker of the
axon initial segment;
magenta, 3-tubulin
(TuJ1), a marker of
the neuronal
cytoskeleton; blue,
DNA (DAPI
staining). The fusion
protein localizes to
dendrites and the
axon (inset) in a
discrete pattern
compatible with
incorporation into
ribosomes and
polyribosomes.
DIVISION OF NEUROSCIENCE
Neurobiology of learning Unit
LTP modulates fractal behaviour of quantal releases at hippocampal synapses
the generation of voltage and Ca2+ oscillations
known to be important for GCPs differentiation.
Spontaneous quantal release series were analysed
before and after the induction of LTP. We found that
the long-term enhancement of quantal release
seen with LTP is accompanied by the occurrence
and/or modulation of a 1/f behaviour, with a significant increase in the fractal exponent. Similarly we
found that α-latrotoxin, a powerful promoter of exocytosis, modulates the 1/f behaviour. Our results
suggest that some pre-synaptic mechanism strictly
related to the dynamics of vesicular pools is actively involved in the generation of 1/f behaviour
and LTP expression.
Analysis of the effects of general anesthetics on
the activity of rat visual cortex
Even if anaesthetics are widely used in the medical
practice, there is still an unresolved issue which relates to their mechanism of action. Rats were anesthetised with either sevofluorane or propofol and
visual evoked potentials, both ON and OFF responses and EEG activity recorded by superficial
electrodes. Results show that while basal cortical
activity is reduced with both drugs, the effects on
VEPs exhibit clear differences, suggesting two very
distinct circuital mechanisms of action.
HCN Channels and cerebellar Maturation
We found that the hyperpolarization-activated
cyclic nucleotide-gated channels HCN 1, 3, 4 are
expressed on Bergmann glia and GCs starting
from early postnatal days. We investigated the role
of these channels by applying specific blockers
(Procolaran and ZD7288) both in vivo and in vitro.
We found that blockade of HCN channels unbalances this process favouring GCs proliferation.
This suggests that the activation of HCN channels
by c-AMP and membrane potential participate in
Novel indicators for synaptic activity in vivo
The establishment of a causal relationships between
the activity of subgroups of synapses is essential for
understanding the basis of animal behaviour. Our laboratory is currently developing a series of innovative
genetically encoded indicators to measure synaptic trasmission both in vitro and in vivo. We are using these tools to define the pattern of synaptic activation in the visual cortex by light.
Antonio Malgaroli
Proteomics of iron metabolism Unit
L-ferritin deficiency is associated to idiopathic generalized seizures and
atypical restless leg syndrome
Our main research interest is to understand the
relationship between brain iron dysregulation and
the process of neurodegeneration. Alterations of
brain iron homeostasis is a hallmark of various
neurodegenerative diseases. Localized iron overload is associated with Alzheimer and Parkinson
Disease and with a group of genetic disorders,
termed Neurodegeneration with Brain Iron Accumulation. Moreover, brain iron deficiency is related
to neurodegenerative processes like Restless Leg
Syndrome and Epilepsy. In particular, last year, we
investigated the effects of L-ferritin deficiency in a
human, demonstrating an association between
alteration of functionality of the iron storage proteins ferritin and Restless Leg Syndrome and
Epilepsy. Cytosolic ferritins are composed of
Heavy (H) and Light (L) subunits that co-assemble
into a hollow spherical shell with an internal cavity
where iron is stored. The ferroxidase activity of the
ferritin H-chain is critical to store iron in its Fe3+ oxidation state, while the L-chain shows iron nucle-
ation properties. We described a patient with a
complete loss of L-ferritin function due to a homozygous mutation (310G>T), located in exon 3
of the L-ferritin gene. We showed that L-chain ferritin was undetectable in primary fibroblasts from
the patient and thus ferritin consisted only of Hchains. Increased iron incorporation into the H-ferritin homopolymer leaded to reduced cellular iron
availability, diminished levels of cytosolic catalase,
SOD1 protein levels, enhanced ROS production
and higher levels of oxidized proteins. Importantly,
key phenotypic features observed in fibroblasts
were also mirrored in reprogrammed neurons
from the patient’s fibroblasts. Our results demonstrated for the first time the pathophysiological
consequences of L-ferritin deficiency in a human
and help to define the concept for a new disease
entity hallmarked by idiopathic generalized seizure
and atypical restless leg syndrome.
Sonia Levi
49
DIVISION OF NEUROSCIENCE
Research Units
Stem cells and neurogenesis Unit
Genetic conversion of mouse and human fibroblasts into induced
neuronal subtypes with therapeutic prospective for neurological disorders
Direct lineage reprogramming through geneticbased strategies enables the conversion of differentiated somatic cells into functional neurons and
distinct neuronal sub-types. We previously identified a set of three transcription factors (Asl1, Nurr1
and Lmx1a) that are sufficient to generate induced
dopamine (iDA) neurons by direct conversion of
skin fibroblasts (Caiazzo et al. Nature, 2011).
These findings lay the ground for a straightforward
and efficient generation of human neurons in vitro
with elaborated functional properties instrumental
for disease modeling and cell-based approaches
of brain repair. In particular, transplantation of iDA
neurons can potentially improve the clinical outcome of Parkinson’s disease by direct replacement
of the degenerated mesencephalic DA neurons.
For instance, transplantation of embryonic-stemcell-derived DA neurons is efficient in restoring
motor symptoms in conditions of DA deficiency
(Kirkeby et al. Cell Reports, 2012). However, current protocols for in vitro differentiation of human
induced pluripotent stem cells (hiPSCs) to generate DA neurons are laborious and time-expensive.
In order to accelerate the overall process, we have
established a fast protocol by the expression of our
three reprogramming factors. With this method, we
were able to generate mature and functional DA
neurons in as few as 21 days, skipping all the intermediate steps of embryoid bodies and rosette
neural precursors (Theka et al., Stem Cells Translational Medicine, 2013). Strikingly, the resulting
neuronal conversion process was very proficient
up to 93% of overall efficiency. hiPSC-derived DA
neurons expressed all the critical molecular markers of the DA molecular machinery and exhibited
sophisticated functional features including spontaneous electrical activity and dopamine release.
This one-step protocol holds important implications
for in vitro disease modeling and is particularly
amenable for exploitation in high-throughput
screening protocols.
Expired by these results, we are currently working
in developing new reprogramming sets of factors
able to induce skin fibroblasts into inhibitory
GABAergic interneurons aiming for a cell therapy
of pharmacological-resistant forms of intractable
human epilepsy.
Vania Broccoli
Figure 6. Wheat germ agglutinin
(WGA) synaptic tracing of
induced DA (iDA) neurons. (A)
iDA neurons were infected with
WGA-IRES-mCherry lentivirus 1
day after sorting and then
replated on mouse MGE primary
cell culture for in vitro analysis.
(B) iDA neurons show a dense
arborization after 21 days in vitro
(DIV) and are able to establish
functional synaptic contacts with
mouse primary cells. (C-F)
Staining for WGA clearly
revealed WGA+/GFP- cells
demonstrating that WGA from
infected iDA neurons was
uptaken from surrounding GAD+
neural cells through functional
synapses. Modified from:
Dell'Anno MT, et al. Remote
control of induced dopaminergic
neurone in parkinsonian rats
[published online ahead of print
June 17, 2014]. J Clin Invest.
doi:10.1172/JCI74664
DIVISION OF NEUROSCIENCE
Molecular genetics of mental retardation Unit
Intellectual Disability (ID) is a common and highly
heterogeneous paediatric disorder characterized
by an IQ lower than 70, with a frequency of 3% in
the population and a very severe social impact.
Family studies have demonstrated a relatively
large number of X-linked forms of ID (XLID) with an
incidence of about 0.9-1.4 over 1000 males. The
work of many laboratories has identified 117 different genes encoding proteins with a large variety of functions that affect the normal cellular processing leading to pre- and/or post-synaptic neuronal terminals dysfunction. The identification of all
the genes responsible for human ID is a though
and ambitious mission but the accomplishment of
that task will shed light about the molecular basis
of ID since genetic defects can be linked through
common molecular pathways. We proposed to
focus genomic studies on specific intracellular
pathways linked to XLID in both ID patients and
murine pre-clinical models. We identified as XLID
genes, GDI1 and RAB39B that encode for two
functionally related proteins involved in vesicular
trafficking: GDI1 encodes for αGDI that, regulating
RAB GTPases, is involved in the spatial and tem-
poral control of intracellular trafficking.
The molecular and behavioural characterisation of
Gdi1 null mouse revealed a complex phenotype
comprehending a marked reduction in the total
number of glutamatergic synaptic vesicles in adult
hippocampus and alterations in different endosomal RAB GTPases leading to deficits in hippocampus-dependent forms of short-term memory. Additionally we are demonstrating that the absence of αGDI allows a misregulation of the glucose metabolism effecting the correct neuronal
functioning, giving us a possible new explanation
on the onset of cognitive disorders.
Furthermore, using genetic, biochemical and behavioural approaches we are unravelling the specific role of RAB39B protein in neuronal intracellular trafficking mediating cognitive function. The
availability of Rab39b null mouse, together with
Gdi1 null mouse, will give us a useful tool to
greatly improve our understanding of the causes
and progression of neurodevelopmental disorders
and to discovery new therapeutic drugs.
Patrizia D’Adamo
51
DIVISION OF NEUROSCIENCE
Clinical Research Units
Acute brain protection, Acute post-operative pain, Drugs
and central nervous system Unit
Clinical research areas:
• Prognosis of diffuse axonal injury after trauma
by MRI (prospective observational study).
• Troponine and BNP after major elective neurosurgery (prospective observational study).
• Cerebral perfusion after major elective neurosurgery in patients submitted to normo- or hyperventilation during surgery (randomized controlled study)
• Participation to the multicenter prospectic database “Neurolink” of patients admitted to neurosurgical Intensive Care Units after severe head
injury.
• Participation to the multicenter prospectic study
“Neuromorfeo” (randomized comparison between total intravenous and inhalation anesthesia during major elective neurosurgery).
• Effects of propofol on “functional MRI” in 4-8 ys
old children submitted to sedation to accomplish neuroradiological examination (prospective
observational study).
• Effects of propofol and thiopental on “functional
MRI” in 1-4 ys old children submitted to sedation to accomplish neuroradiological examination (randomized controlled study).
• Physiopathology of mechanical ventilation during ENT surgery with laser-proof endotracheal
tubes (prospective observational study).
• Systemic complications during catharact surgery under local anesthesia (prospective observational study).
• Assessment of airway protection during sedation (prospective interventional study)
• Study of complications in children sedated for
neuroradiologic procedures (prospective observational study).
• Sedation in gastroenterology procedures.
Analysis of a large database.
• Acute postoperative pain: ERAS (Enhanced recovery After Surgery).
Luigi Beretta
Cognitive neuroscience Unit
This is a multidisciplinary Unit which combines
theoretical knowledge and research skills from different backgrounds (neurology, neuropsychology,
linguistics, cognitive psychology), with the general
aim to investigate the neural mechanisms of language, memory and high-order cognitive functioning, particularly decision-making and social
cognition processes. To this purpose, we use
and integrate different experimental approaches,
including behavioural studies in normal subjects
and in neurological patients, brain imaging (magnetic resonance techniques and positron emission tomography), and neurophysiological investigations based on event-related potentials (ERPs),
transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS).
Stefano F. Cappa
Experimental neurosurgery Unit
Clinical and basic research in neurosurgery:
• Results of Gamma Knife Radiosurgery in the
treatment of pituitary adenomas
• Multisession Gamma Knife treatment for perioptic tumors
• Gamma Knife treatment for vestibular schwannomas: analysis of vestibular and acoustic function
• Experimental studies on neuroregeneration with
collagen scaffold and autologous olfactory cell
implant
• Collaboration with Prof. Comi, Dott. Martino,
Dept. of Neurology, INSPE, Dott. Ciceri Dept. of
Hematology OSR, in the design of clinical trial
regarding cell therapy with blood monocytes in
traumatic spinal cord injury
• Role of cancer stem cells in brain tumours biology (in collaboration with Dott. Galli, SCRI OSR)
• Study of pathogenetic mechanisms involved in
human pituitary adenomas (in collaboration with
Prof. G.K. Stalla, Department of Endocrinology,
Max Planck Institute of Psychiatry, Munich, Germany)
• Molecular biology and genetics of chordomas
(in collaboration with Prof. P. Riva, Department
of Biology and Genetics, Medical Faculty, University of Milan)
• Molecular biology and genetics of craniopharyn-
DIVISION OF NEUROSCIENCE
giomas (in collaboration with Prof. P. Riva, Department of Biology and Genetics, Medical Faculty, University of Milan)
• Microanatomical studies for new skull base approaches and relative reconstructive techniques
(in collaboration with Prof. A.J. Caputy, Prof. F.
Roberti, George Washington University Neuro-
logical Institute, Washington DC, USA)
• Study of microcerebral blood flow (in collaboration with Prof. Agabiti Rosei, Prof. D. Rizzoni,
Dott. G. Boari, Clinica Medica, Department of
Medical and Surgical Sciences, University of
Brescia)
Pietro Mortini
Eye repair Unit
CLINICAL RESEARCH
1. In vivo corneal confocal microscopy of corneal
nerves: normal anatomy and pathological
changes in corneal infections and neurologic
diseases.
2. Epidemiology of corneal neovascularization.
3. Retrospective evaluation of the safety and efficacy of autologous cultivated limbal stem cells
transplantation for restoration of corneal epithelium in patients with limbal stem cell deficiency
due to ocular burns.
4. A 10-year retrospective study of patients treated with polyhexamethylene biguanide (PHMB)
for Acanthamoeba keratitis to develop PHMB
as the first approved drug medicinal product
(orphan drug). Project funded by the EU under
the Seventh Framework Programme (GA N
305661) in collaboration with the Moorfields
Eye Hospital, London (UK).
5. Release of neuromediators in the lacrimal fluid
after corneal surgery in patients affected by
keratoconus.
TRANSLATIONAL RESEARCH
1. Role of various macrophage populations in animal models of corneal neovascularization, in
collaboration with Dr. R. Mazzieri and Prof. L.
Naldini.
2. Safety and efficacy of NK1Ra as a treatment of
corneal neovascularization.
3. The role of corneal nerve morphology as a biomarker for diabetes nephropathy and retinopathy, in collaboration with Dr. G. Zerbini.
4. Proteomic and cellular fingerprint of corneal
neovascularization.
5. Local anti–TNF therapy in ocular surface inflammation with implications for conjunctival scarring diseases: the project preludes clinical application.
6. The effect of corneal inflammation on central
nervous system (trigeminal ganglion) in a
mouse animal model with in vivo MRI and ex vivo techniques, in collaboration with Dr. L.
Chaabane.
7. Retrospective study on the incidence of
corneal neovascularization in a population presenting at the Cornea and Ocular Surface Unit.
8. Modulation of nerve growth factor (NGF) levels
and related pathways in the retina following optic nerve crush for developing new therapies.
TRIALS
1. Multicentric European Clinical trial (REPARO
STUDY), phases I-II, on the safety and efficacy
of recombinant NGF for the treatment of neurotrophic keratitis
2. Monocentric observational study of corneal
nerves, electrophysiology of peripheral nerves
and clinical evaluation in peripheral neuropathies (CONFONEUR)
Paolo Rama
53
DIVISION OF NEUROSCIENCE
Clinical Research Units
Functional neuroradiology Unit
The Unit is composed by different groups applying advanced MR techniques to study brain
structure and function during physiological and
pathological development, during normal and
pathological aging, in neuro-oncology and neurovascular diseases. The neuropediatric group
studied myelination in normal and preterm
neonates; diffusion techniques have been employed to follow the modification of white matter
over time. Functional MRI has been used to investigate auditory and language areas and their
maturation over the time (in collaboration with In
vivo Human molecular and structural neuroimaging Unit). fMRI has been used to investigate lateralization of the mirror neuron system in normal
adult subjects and to verify the influence of experience on some specific motor functions, like digit
skill, in musicians (in collaboration with Experimental Neurophysiology Unit). Volumetric techniques
(VBM analysis) and diffusion based techniques
have been employed to study subjects affected
by neurodegenerative diseases like MCI, AD and
FTD, trying to identify early marker of disease associated with the conversion of MCI to dementia
and to characterize selective involvement of brain
areas in FTD (with Cognitive Neuroscience and
Neuroimaging research Unit). The neurodegenerative changes related to motor neuron disease
have been studied in Patients with ALS and PLS.
The vascular group applied new high resolution
techniques to identify vulnerability characteristics
in patients with severe carotid stenosis and their
correlation with cerebral ischemia and to test new
contrast media. In collaboration with Sleep Medicine Unit, combined neuropsychologic testing
and MR VBM analysis was used to assess cognitive deficits and the corresponding brain morphology changes before and after treatment in patients with OSA)
The neuro-oncology group focused on the clinical
validation and utility of tractography, and on the
development of new algorithm based on tensorial
diffusion, potentially useful to better characterize
cellular and extracellular components of brain tumors. Other topics like the study of inflammatory
diseases or optic nerve degeneration have been
performed in collaboration with Neuroimaging Research Unit, Neuroimaging of CNS White Matter
Unit, Eye Repair Unit.
Andrea Falini
Figure 7. Whole brain language network tractography using naming fMRI activations as seed region of interest,
based on high-angular-resolution diffusion imaging (HARDI) in a Patient harboring a brain tumor.
DIVISION OF NEUROSCIENCE
In vivo Human molecular and structural neuroimaging Unit
Researches addressed brain functional and molecular parameters in neurodegenerative conditions by using PET techniques. We assessed the
amyloid load using PET and fluorinated tracers in
subject with MCI/prodromal AD and compared
with FDG PET functional derangements. These
research results support divergent pathways for
these biomarkers that might guide clinical applications.
The clinical expression of Alzheimer’s disease
(AD) is thought to occur as neuropathology exceeds the brain “reserve capacity”. [11C]-MP4
and PET measures of the cholinergic system allowed the estimation of AchE activity in AD and
MCI subjects and the testing of reserve proxies,
such as education and occupation, as modulator
factors on the cholinergic system. We found significant positive correlations in the left hippocampus, lateral temporal cortex and posterior cingulate gyrus, suggesting that reserve proxies modulate specific cholinergic projections involved in
learning and memory.
We validated an optimized voxel-based SPM
analysis based on a new atlas for normalization to
be applied at single subject level for 18FDG PET
studies in neurodegenerative disease associated
with cognitive decline and dementia. We showed
high sensitivity and specificity in the detection of
brain functional alterations at the single subject
level. This optimized SPM methods for FDG PET
analysis, was applied in series of patients with
neurodegenerative disorders and brain functional,
clinical and neuropsychological correlations were
obtained, useful for research purposes and clinical applications.
MRI structural measurements were applied to
study morphometric changes in developmental
disorders (subjects with sporadic and genetic association dyslexia, subjects with DCDC2 mutation
causing altered neuronal migration and associated cognitive disturbances). The results provided
evidence for strucutural alterations of neural systems in these individuals supporting reading and
specific cognitive processes.
Daniela Perani
Figure 8. Correlation between acetylcholinesterase (AChE) activity and education (LEFT) and occupation
(RIGHT) proxies. The images show regions of interest of significant positive correlation, superimposed
on a standard anatomical template, and the corresponding scatterplot of AChE activity against individual
scores. Modified from: Garibotto, V et al. Neurobiol. Aging: 2013; 34(11): e13-e18 doi: 10.1016/j.neurobiolaging.2013.05.020.
55
DIVISION OF NEUROSCIENCE
Clinical Research Units
Neuroothology Unit
Four papers were published during 2013 on topics related to inner ear disorders.
One more paper on Vestibular Schwannomas has
been accepted and will be soon published. Bruno
Colombo and Roberto Teggi participated in 2013
as guest editors of the book Vestibular Migraine
and related disorders that will be published by
Springer Edition during 2014.
Audiovestibular research has at present the following lines of research:
• Study of the phenotypes of episodic vertigo, in
a consortium of the Barany Society (Principal Investigator Alexandre Bisdorff)
• Genetics of Menière’s Disease: the study is carried on both in collaboration with Prof Lopez Escamez (Centre Genyo – Almeria) and with Prof
Manunta for genetics of ionic transporters.
• Phenotypes and genetics of Vestibular Migraine: a collaboration has been carried on both
with Dr Bruno Colombo and Prof Paolo Manunta. A grant of the Italian Headache Society has
been obtained for the purpose
• Functional MRI in patients with Vestibular Migraine, in collaboration with Bruno Colombo and
Massimo Filippi
• S-Loreta EEG mapping in patients with chronic
tinnitus in collaboration with MAGICS (Chief Dr
Leocani).
Cocaine Induced Midline Destructive Lesions
(CIMDL) research on with the following projects:
• Position paper concerning CIMDL scheduled to
be published in 2014 (accepted on Rhinology
Journal)
• Multicenter study on links between CIMDL and
autoimmunity.
• Analysis of genetic polymorphisms possibly associated with CIMDL through exome sequencing in collaboration with the San Raffaele Center
for Translational Genomics and Bioinformatics.
A government grant from the Italian Dipartimento
Politiche Antidroga della Presidenza del Consiglio has been obtained for the purpose.
Mario Bussi
Psychiatry and clinical psychobiology
We continued our research activities at the interface between neuroscience and behavioral disorders, to increase knowledge and develop effective diagnosis and treatment options in the broad
field of Psychiatry and Clinical Psychobiology.
We provided the first reports on the effects of the
simple cation lithium, the mainstay of the treatment of Bipolar Disorder, on white matter microstructure. We showed that the less active
GSK-3β rs334558*C gene promoter variant, and
the long-term administration of the GSK-3β inhibitor lithium, were associated with increases of
DTI measures of axial diffusivity in several WM
fiber tracts contributing to the functional integrity
of the brain, thus counteracting the detrimental influences of BD on WM structure of the brain. We
also showed that widespread changes of white
matter microstructure are common to ObsessiveCompulsive Disorder, and a target for drug treatment.
Using translational approaches in the study of
gene-environment interactions, we showed that
COMT genotype biases neural correlates of empathy and perceived personal distress in schizophrenia; and contributed to large international
studies of genome-wide association of OCD, and
of the heritability of OCD and of Tourette syndrome. We also continued the reasoning about
the role of intracellular pathways which are part of
the biological clock machinery in mood disorders.
We continued the profiling of psychopatological
conditions by studying social interactions, executive functioning, and startle reflex in eating disorders; reality monitoring deficits in schizophrenic
and affective psychosis; and neural responses to
moral valence decision in depression.
Refining diagnostic and treatment options for our
patients, we studied the cortical effects of electroconvulsive therapy by means of transcranial magnetic stimulation and electroencephalography in
severe depression; Theory of Mind interventions
for outpatients with schizophrenia; and current
drug options to achieve remission in mood disorders and psychotic psychiatric conditions.
Finally, we continued our commitments within the
frame of the EU funded MOODINFLAME research
project, investigating the clinical and brain imaging
correlates of neuroinflammation in mood disorders.
Francesco Benedetti
DIVISION OF NEUROSCIENCE
Figure 9. White matter areas where carriers of a low activity variant of the glycogen synthase kinase 3-b
promoter gene showed significantly higher values of axial diffusivity than homozygotes for the wild variant. Voxels of significant group differences are mapped on the mean fractional anisotropy template of
the studied sample. Cover image courtesy of Dr Francesco Benedetti & Dr Irene Bollettini, Ospedale
San Raffaele, Division of Neuroscience, Milano, Italy. Published in: Neuropsychopharmacology: 2013;
38(2): 313-327. doi: 10.1038/npp.2012.17
Sleep medicine
The main objective of our research program was
the evaluation of pathogenetic mechanisms and
treatment strategies of abnormal motor activity
during sleep. In particular, we studied patients
with Restless legs syndrome (RLS), periodic leg
movements during sleep (PLMS), and REM sleep
behavior disorder (RBD).
We compared night-to-night variability of PLMS
and Periodicity indices in patients with RLS or periodic limb movement disorder (PLMD). In both
patient groups, the Periodicity index showed a
significantly lower degree of variability than that of
PLMS index, being >6.5 times lower in RLS patients and 2 times lower in PLMD patients. These
data support the use of the Periodicity index in the
evaluation of PLMS in RLS and PLMD and indicate that this parameter seems to be more stable
than the widely used PLMS index which has higher night-to-night variability.
Dopamine agonists (DAs) represent the first-line
57
DIVISION OF NEUROSCIENCE
Clinical Research Units
treatment in RLS; however, in the long term, a
substantial proportion of patients will develop
augmentation, which is a severe drug-related exacerbation of symptoms and the main reason for
late DA withdrawal. We evaluated consecutive
outpatients affected by RLS with clinically significant augmentation during treatment with immediate-release DA. A switchover from immediate-release DAs to the long-acting, extended-release
formula of pramipexole was performed and in all
patients resolution of augmentation was observed
within two to four weeks. This observation supports the hypothesis that the duration of action of
the drug plays a key role in the mechanism of
augmentation.
Idiopathic RBD is a parasomnia characterized by
dream enactment and is commonly a pre-diagnostic sign of parkinsonism and dementia. We
participated to a multicenter case-control study to
assess the family history in RBD. A total of 632
participants (316 patients, 316 controls) were recruited. We found increased odds of proxy-reported family history of presumed RBD among individuals with confirmed idiopathic RBD. This suggests the possibility of a genetic contribution to
this parasomnia.
We analyzed sleep characteristics in drug-free
RBD patients compared to controls, and we evaluate the changes following the long-term use of
clonazepam in RBD patients. Slow transient electroencephalography (EEG) events were increased
in RBD, while fast transient events decreased in
these patients. After clonazepam treatment, sleep
stages 1 and 2 NREM instability significantly decreased and the duration of EEG transients significantly decreased. A decreased sleep instability
after clonazepam might indicate a factor contributing to the restorative properties of sleep in
RBD.
Luigi Ferini-Strambi
Clinical psychology
The Unit of Clinical Psychology developed research programs according to the characteristics
of each Sub-Unit:
1. Personality and Personality disorders: different
aspects of emotional and behavioral dysregulation remained the main topic of interest and were
studied both in non-clinical and clinical subjects.
According to the plasticity of personality over
time, in different periods of life, studies were conducted in adolescent and adult subjects.
In particular, predictive characteristics of DSM-5
Section III traits and psychopathy measures were
assessed in nonclinical adolescents and adults,
as well as in adult clinical participants (Prof. A.
Fossati). According to the increasing interest in
the role of mindfulness both in pathogenesis and
treatment of borderline personality disorder, the
hypothesis of a failure in mindfulness was investigated.
Results showed that mindfulness capacities were
reduced in personality disorders in general, but
the most important difficulties were found in borderline subjects. Interest in mindfulness was a
natural expansion of the area of mentalisation
present in previous research projects and still going on. The project on elicitation of emotions in
borderline subjects using standardized videoclips
was extended with the insertion of psychophysiological characteristics (HRV- Heart Rate Variability)
and saccadic eye movements. The collaboration
with the Unit of Sleep Medicine made that possible.
2. Alcohol addiction (Dr. M. Movalli): a pilot study
on the effect of an innovative treatment based
on the Skills Training of the Dialectical Behavior
Therapy (DBT) was started. Preliminary results
were promising and showed how mindfulness capacities, together with personality characteristics,
play a relevant role in relapse prevention.
3. HIV infection (Dr. R. Visintini): the multicenter
national study coordinated by the Health Ministry
(National AIDS Center -Istituto Superiore di Sanità)
on the vaccine for HIV infection (TAT) was going
on under the direction of our Unit as to the psychological area. Neuropsychological tests were
administered and preliminary findings showed
that in a sub-population of subjects signs of precocious brain atrophy were detectable.
Cesare Maffei
DIVISION OF NEUROSCIENCE
Motor function rehabilitation
The 2013 research activities focused on 1) the effectiveness of Action Observation (AO) treatment
in rehabilitation of subjects with neurological diseases, 2) the effect of AO on postural control and
balance, 3) the connection between motor training and language and 4) the study of muscle innervation zone (IZ) and muscular painful spot.
The second activity was about the possibility to
use cognitive facilitation (such as AO) in the rehabilitation of postural and balance disorders was also studied in non-pathologic subjects. These
studies addressed the feasibility of using cognitive
facilitation to improve some implicit aspects of human movement (as balance and postural control).
The first activity was developed in collaboration
with the Functional Unit of Quantitative Neuroimaging of San Raffaele Hospital (OSR) and the
Department of Neurology OSR. Two RCT have
been started. The first one was about the effectiveness of AO for improving the gait of subjects
with Parkinson disease and freezing. This study
involved both clinical measures and the study of
brain cortical activation by fMRI. These were collected prior to and after a period of physiotherapy
treatment based on AO of videos inherent to the
situation that normally provokes the freezing phenomenon or sham videos.
The second study addressed the rehabilitation of
hand dexterity in subjects with multiple sclerosis.
In this case the subjects in the experimental
group look at videos related to functional hand
tasks. Even in this case the outcomes were both
clinical measures and measures of fMRI.
The third activity was inherent the connection between motor performance and cognitive processes, such as language. The study was about the
effect of linguistic training on hand motor abilities
congruent at the trained task. The study was realized in collaboration with the experts of language
of the Psychology Faculty of the Vita-Salute San
Raffaele University and using the OSR Lab of
movement analysis for the acquisition and analysis of the hand kinematics.
The fourth activity was developed in collaboration
with the SUPSI University of Lugano (CH). It was
inherent the study of the relationship between
muscle IZ and muscular painful spots, using matrix surface electromyography.
Roberto Gatti
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DIVISION OF NEUROSCIENCE
Introduction by the Director
INSPE
Institute of Experimental Neurology
The Institute of Experimental Neurology (INSPE) constitutes one of the major European institutes primarily dedicated to translational research in the neuroscience field. The overall ambition is to conjugate high
level of basic research with the specific competences in pre-clinical and clinical research. This is achievable considering that INSPE includes both research laboratories and the Neurological Department of the
San Raffaele Scientific Institute. Inflammatory and neurodegenerative disorders of the central and peripheral nervous system, stroke, spinal cord nerve and traumatic injures represents the primary targets of
the INSPE research.
The primary goal is to better understand the molecular mechanisms that sustain inflammatory and degenerative pathogenic mechanisms underlying neurological disorders so to identify therapeutic targets,
validate in co-operation with pharma companies new treatments, develop new disease biomarkers for
both clinical trials and patients monitoring. The neurological department is deeply involved in the definition of new treatment algorithms for stroke, inflammatory and neurodegenerative diseases. The molecular and functional bases for central and peripheral nervous system recovery processes and the potential
to modulate them by cellular and gene therapy and by specific rehabilitation interventions are another
area of interest of INSPE.
The INSPE laboratories spans on four different levels in DIBIT2 buildings. One floor is dedicated to neuropathology, experimental neurophysiology, neurogenetics of monogenic and complex diseases. Another
floor is dedicated to basic and clinical neuroimmunology, neurobiology, neural stem cell research and
neuroembriology. The third floor is focused on neuroimaging of neuroinflammatory and neurodegenerative disorders. The fourth floor includes labs on experimental imaging and molecular biology. Other laboratories involved in behavioral research and in signals that regulate myelination and in clinical
neurophysiology are also part of the Institute. Finally the MAGICS Center which studies effects on magnetic stimulation of the brain complete the research area.
DIVISION OF NEUROSCIENCE
Research Units, INSPE
Experimental neuropathology
Defining peripheral nerve environment in amyotrophic lateral sclerosis
Growing evidence indicate that alterations within
the peripheral nervous system (PNS) are involved
at an early stage in the amyotrophic lateral sclerosis (ALS) pathogenetic cascade. Moreover, the
hypothesis that some of the peripheral nerve environment (PNE)-resident cells, such as endothelial
or Schwann cells, could be involved in or could
“sense” an early axonal damage is to be considered.
Our aim is to characterize in details the natural
history of the PNS damage in the hSOD-1G93A
ALS rat model using both in vivo and ex vivo readouts. We will obtain an exhaustive functional and
pathological description of the PNS involvement in
hSOD-1G93A ALS rat model that could be useful
for a reliable and quantitative analysis in preclinical
research in ALS. Moreover, human motor nerve
diagnostic biopsies previously obtained for diagnostic purposes from ALS patients will also be
characterized and studies using different readouts.
Our studies will establish the PNS signature of the
disease, shedding new lights into ALS pathogenesis and providing a rationale basis for translating
future systematic functional and pathological
studies aimed at unrevealing the PNS involvement
in human ALS.
We believe that our combined, innovative rat-human approach will provide rationale for the development of new therapeutic approaches and to
identify new diagnostic biomarkers.
Angelo Quattrini
Experimental neurophysiology
Our unit is involved in the development and validation of non invasive neurophysiological techniques,
such as electroencephalography and evoked potentials in assessing and monitoring neurological
diseases. We also investigate the usefulness of
neurostimulation techniques (deep brain stimulation, transcranial magnetic-TMS and direct current
stimulation-tDCS) with the aim of promoting therapeutic neuromodulation and brain plasticity. These
objectives are searched through a translational approach, with application in people with neurological
disorders and animal models.
During 2013, we explored functional interhemispheric motor connections using TMS in Parkinson’s disease, demonstrating different degrees of
involvement according to disease severity (Spagnolo et al. 2013). We applied topographic source
analysis of cognitive event related potentials to the
Stroop test, demonstrating a more severe involvement of executive function in amyotrophic lateral
sclerosis with respect to primary lateral sclerosis
(Amato et al 2013). Our results suggest that the
covert version of the Stroop task used in the present study, may be useful to assess cognitive state
in the very advanced stage of the disease, when
other cognitive tasks are not applicable. The cognitive event-related potentials to the Stroop test
have been integrated on anatomical brain reconstructions from magnetic resonance imaging in
order to provide a better individual source localization to be further applied in the investigation of
cognitive involvement in neurological disorders
(Gonzalez-Rosa et al 2013). In pre-clinical research, we used EEG to demonstrate dysfunction
of brain circuits involved in the genesis of resting
EEG in models of epilepsy, such as those associated with synapsyn I/II/III knock-out (Cambiaghi et
al Neuropharmacology 2013) and to investigate
mechanisms of rapamycin treatment in a mouse
model of tuberous sclerosis complex (Cambiaghi
et al Neuropharmacology 2013).
On the side of brain stimulation as a treatment or
neurological disorders, we tested safety and potential efficacy of a newly developed method of
non invasive transcranial brain magnetic stimulation in an open label study on motor symptoms in
Parkinson’s disease (Spagnolo et al. 2013) and
we applied this technique in a case of progressive
supranuclear palsy with progressive aphasia
(Spagnolo et al. 2013). We also implemented the
application of non invasive neuro-stimulation techniques in stroke. In particular, in an explorative pilot study we tested the efficacy of different protocols of deep repetitive transcranial magnetic stimulation to improve naming in chronic post-stroke
aphasia (Chieffo et al 2013). Moreover, we evaluated whether different stimulation protocols of
transcranial direct current stimulation could have a
neuroprotective effect in the acute phase of experimental brain ischemia (Peruzzotti Jametti et al
2013).
Letizia Leocani
61
DIVISION OF NEUROSCIENCE
Research Units, INSPE
Molecular genetics of behaviour
Our laboratory has focussed for a number of
years on the role of the Ras-ERK intracellular cascade in neuronal cell signalling and behavioural
plasticity. Once neurotransmitter receptors are activated, specific guanine exchange factors (GEFs)
are able to catalyse the exchange of GDP for GTP
on Ras proteins, thus activating this class of small
GTPases. Activated Ras proteins then stimulate
the core element of the signalling pathway, the
Ras-MEK-ERK protein kinase cascade which is
crucially involved in transducing signals to the nucleus, hence controlling chromatin remodelling
and gene expression, key steps involved in various forms of behavioural plasticity.
In recent years, it has become clear that deregulation of this signalling pathway in the brain may
lead to brain dysfunction.
The work of our laboratory in 2013 has focussed
on the cellular mechanisms of L-DOPA induced
Dyskinesia (LID), a severe disorder associated to
the current pharmacotherapy of Parkinson’s Disease (PD). The key brain structure implicated in
LID is the dorsal portion of the striatum, the input
nucleus of the basal ganglia system. During this
year we have extended previous work of the labo-
ratory on Ras-GRF1, a neuronal specific activator
of Ras proteins, by showing that a specific ablation of this factor in the striatum is sufficient to significantly attenuate LID symptoms in mice. In fact,
similarly to the Ras-GRF1 KO animals, Ras-GRF1
knockdown mice in the striatum appear to be protected toward abnormal involuntary movements
(AIM), the behavioural correlate of dyskinesia in
rodents, in a neurotoxin model of LID. In addition,
we have shown that Ras-GRF1 and ERK signalling modulate synaptic plasticity processes in
the striatum, including long-term potentiation
(LTP), in a complex manner and that in the PD
neurotoxin model, chronic L-DOPA administration
causes a substantial synaptic reorganisation, likely representing the cellular correlate of LID.
Finally, we have patented cell permeable peptides
(CPPs) able to modulate ERK signalling in vivo.
Such CPPs are able to alter several ERK mediated behavioural processes, including responses to
psychostimulants and to L-DOPA in dyskinetic
animals, providing a new interesting approach to
therapies of neuropsychiatric disorders.
Riccardo Brambilla
Neuromuscular repair
Our unit is interested in the role of adhesion in
neuromuscular regeneration, focusing on integration of cellular and extracellular signals in order to
regulate development, function and regeneration
of muscles and nerves.
We recently reported the role of vimentin, a cytoskeleton component of PNS neurons, in the
regulation of peripheral nerve myelination. Vimentin modulates the levels of Neuregulin 1 type
III through the shedding activity of the TACE enzyme.
We also reported evidence that proper peripheral
nerve development and Schwann cell-axon interaction is regulated by the nuclear molecule Jab1.
Loss of Jab1 in Schwann cells compromises cell
proliferation, differentiation and survival, causing a
dysmyelinating peripheral neuropathy. Jab1 integrates and modulates laminin2-derived signals in
Schwann cells, thus suggesting to be involved in
the pathogenesis of Congenital Muscular Dystrophy
Finally, we provided evidence that stem cell
mesoangioblasts, engineered to release miniagrin, can ameliorate muscular dystrophy in
mouse model of Congenital Muscular Dystrophy
type 1A (CMD1A). Mini-agrin links laminin2 receptors expressed by skeletal muscle to laminin isoforms overexpressed in the absence of laminin2.
Stefano Carlo Previtali
DIVISION OF NEUROSCIENCE
Figure 10. abnormal axon sorting
in nerves of Jab1 null mice
Neuroimmunology Unit
The central nervous system (CNS) has the intrinsic capability to repair itself when injured. Over the
years a series of molecular and cellular innate repair mechanisms have been discovered and their
ability to prevent irreversible tissue damage and irreversible neurological deficits has been characterized.
Among cellular mechanisms, those sustained by
neural stem/precursor cells (NPCs) - the self-renewing and multipotent cells of the CNS capable
of driving neurogenesis and gliogenesis during
development and adult life - play a crucial role. As
a matter of fact, both endogenous and transplanted NPCs are capable of migrating into damaged
CNS areas to promote functional and structural
tissue repair via different mechanisms of action
spanning from cell replacement to the release of
soluble neuroprotective molecules (i.e. bystander
effect).
The Neuroimmunology Unit is particularly interested in understanding the role of endogenous
NPCs in both the developing and the adult
healthy CNS in order to develop alternative therapies based on NPC transplantation for acute and
chronic CNS inflammatory disorders characterized by irreversible neurodegeneration (i.e. multiple sclerosis, stroke and spinal cord injury).
Endogenous NPCs in the adult brain. We are
studying the role of microglia - the immune relevant cells of the CNS - during brain development.
So far, we obtained results indicating that microglia patrol and protect - possibly via their
phagocytizing activity - neuronal precursor positioning within the cortex.
Transplantation of adult NPCs. We have found
that both adult and embryonic-like NPCs are able
to protect from inflammation-induced neurodegeneration - as that occurring is ischemic stroke
and multiple sclerosis - via a series of different
therapeutic strategies encompassing both immunomodulation (by restraining DC function) and
neuroprotective mechanisms. Among neuroprotective mechanisms, we found that NPCs protect
neurons from excitotoxicity by up regulating glutamate transporters on endogenous astrocytes and
oligodenrdocytes by secreting neurotrophic factors such as LIF.
Gianvito Martino
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DIVISION OF NEUROSCIENCE
Research Units, INSPE
Figure 11. GFP positive miPSC colonies expressing SSEA1 marker. Shown are GFP positive miPSC
colonies (green) stained with SSEA1 (red). Nuclei are counterstained with dapi (blue).
Clinical neuroimmunology
The Group of Clinical Neuroimmunology is active
in both experimental and clinical neuroimmunology with the aim to have a bi-directional transfer of
scientific questions and experimental data between the two. Concerning our work on mice,
during 2013 we have continued our gene therapy
approach to deliver cytokines in the inflamed brain
by completing the studies on IL-35 and investigating also the effects of IL-27. Both of them are able
to modulate microglia and modify the clinical and
neuropathological features of neuroinflammation,
but with different efficiency and slightly different
mechanisms. Further, by using IL-4 as comparison, we highlighted a new, suppressive role for IL-
6. Concerning microvesicles, in humans we have
characterized their release from a microglia cellline, learning their dependence from the stimulation of the P2X7 purinergic receptor. From a clinical point of view, we studied the number and relation to clinical and para-clinical data of microvesicles in the CSF in demented patients. Finally, we
immunologically profiled patients affected by major psychoses such as schizophrenia, major depression, and bipolar disorder. We found that depressed patients display an M1 activation of
monocytes in the blood. Further studies on this issue are ongoing.
Roberto Furlan
DIVISION OF NEUROSCIENCE
Figure 12. A human microglia cell line stimulated with ATP modifies its shape and starts to release shed
vesicles in a polarized manner.
Immunobiology of neurological disorders
Our lab studies the role of the immune system in
the physiology and pathology of central and peripheral nervous system. To tackle this issue we
make use of complementary disciplines, including
immunology, neurobiology, histology, animal modelling, cellular and molecular biology, genomics,
bioinformatics and systems biology. Thus, taking
the moves from clinical observations and from human samples (blood or cerebral tissue), our research explores the activity of immune/glial/neuronal cells in vitro, sums up the high-throughput
generated data with systems biology approaches,
goes to the in vivo mouse models, until it is ready
to go back to the clinic via the identification of
novel diagnostic and prognostic biomarkers and
the proposition of new therapeutic targets and
approaches.
Recently, we developed a statistics and bioinformatics platform for the analysis of high-throughput
transcriptomics data in multiple sclerosis. The
gender-based functional genomics analysis al-
lowed the definition of biomarkers for multiple
sclerosis in peripheral blood and emphasized the
role of the transcription factor SP1 in neuroinflammation (Menon et al J. Autoimmunity 2012). During the year 2013 we isolated transcriptional signatures in peripheral blood which stratified distinct
multiple sclerosis stages and identified a series of
novel transcriptional regulators as potential therapeutic targets.
Regarding the inflammatory processes in peripheral nervous system, during the last years we acquired novel information about the physiology of
skeletal muscle and extended this knowledge to
the study of idiopathic inflammatory myopathies.
Starting from evidences published by our group
(Colombo et al J. Neuropath. Exp. Neurol. 2011,
J. Neuroimmunology 2012, Neuropath Appl Neurobiol 2012), in 2013 we demonstrated that neurotrophins regulate myogenesis and tissue regeneration in skeletal muscle (Colombo et al. J.
Pathology 2013). Moreover, we found that in in65
DIVISION OF NEUROSCIENCE
Research Units, INSPE
flammatory myopathies infiltrating T lymphocytes
and macrophages produce the neurotrophic factor BDNF and get localized near regenerating myofibers which express the neurotrophin receptor
p75NTR(Colombo et al. J. Pathology 2013), supporting the hypothesis of a tissue-protective immune response in inflamed skeletal muscle.
Cinthia Farina
Neuroimaging research Unit
Main achievements
• Normal brain. The organization of functional
brain networks differ between genders, likely
contributing to the abnormalities detected in
diseases with a gender prevalence.
• Multiple sclerosis. In MS, imaging features of
cortical lesions differ from those of white matter
(WM) lesions and may reflect neuronal damage
and microglial activation.
• Both trans-synaptic degeneration secondary to
optic nerve damage and Wallerian degeneration
due to T2 lesions contribute to optic radiation
damage in MS.
• Cervical cord voxel-based assessment contributes to a better characterization of the clinical
heterogeneity of MS.
• In MS, cognitive reserve independently protects
against disease-related cognitive decline over
and above brain reserve. Lifestyle choices protect against cognitive impairment independently
of genetic factors.
• Migraine. Cortical abnormalities occur in migraine representing the results of a balance between an intrinsic predisposition and diseaserelated processes.
• Dementia. Early onset Alzheimer’s disease patients had a more severe and distributed WM
damage relative to late onset AD.
• The nonfluent and semantic variants of primary
progressive aphasia share an overlapping pattern of dorsal and ventral WM pathway abnormalities. Variant-specific WM changes were also found, contributing to the specific language
deficits.
• Resting state fMRI abnormalities in the behavioural variant of frontotemporal dementia
(bvFTD) involve the salience, default mode and
frontoparietal networks. Functional changes distinguish bvFTD from AD.
• Graph analysis showed that global and local
functional networks are altered in bvFTD, suggesting a loss of efficiency in information exchange between both distant and close areas.
• Amyotrophic lateral sclerosis. In ALS, an increased parietal connectivity may have a role in
maintaining cognitive efficiency despite structural frontotemporal injury.
• WM damage to interhemispheric, limbic and associative tracts contribute to cognitive deficits in
primary lateral sclerosis.
• Parkinson’s disease. In PD, WM abnormalities
beyond the nigrostriatal system accumulate with
increasing motor and nonmotor severity.
• WM damage in PD patients with GBA gene mutations may have an impact on the clinical manifestations, including cognitive impairment.
Massimo Filippi
Neuroimaging of CNS white matter
Research activity
Multiple Sclerosis
• We evaluated the role of brain and cognitive reserve in limiting onset of cognitive deficits in
cross-sectional and longitudinal investigations.
• We assessed the contribution of involvement of
strategic regions of the gray matter (GM) and
white matter (WM) to the pathogenesis of fatigue and depression.
• In patients with pediatric MS, we found a peculiar pattern of structural involvement of the GM
and WM in posterior regions of the brain.
• Differently from adult MS patients, pediatric MS
patients experience only limited abnormalities of
resting state (RS) functional connectivity (FC)
and internetwork connectivity.
• Using voxel-wise analysis, we defined the contribution of structural damage to the cerebellar
peduncles to cerebellar deficits in a large cohort
of patients.
• Deficits in memory and visuospatial learning correlate with regional hippocampal atrophy.
• In a 13-year longitudinal study, we found that
baseline measures of GM damage predicted
worsening of clinical disability and cognitive
deficits in patients with relapse-onset MS.
• Modifications of RS FC of cognitive-related re-
DIVISION OF NEUROSCIENCE
gions predicted the persistence of cognitive rehabilitation effects in patients with relapsing-remitting MS.
• Both trans-synaptic degeneration secondary to
optic nerve damage and Wallerian degeneration
due to local T2 lesions contribute to optic radiation damage.
• We developed two different methods for the assessment of regional cervical cord atrophy.
Migraine
• Similarly to adult patients, pediatric patients with
migraine have GM structural abnormalities involving regions of the pain matrix.
• Patients with Fahr’s disease and migraine have
structural and functional abnormalities similar to
those observed in migraineours.
• We explored the patterns of cortical thickness
and cortical surface area abnormalities in patients with migraine.
Pediatric Brain Injury
• Using RS MRI and diffusion tensor imaging
(DTI), we identified the predictors of clinical improvement following constraint-induced movement therapy (CIMT) in pediatric patients with
chronic hemiplegia.
Neuropathies
• In patients with peripheral neuropathy, RS FC
modifications extend beyond the sensorimotor
network and involve other sensory and cognitive
networks.
Maria Assunta Rocca
Human inherited neuropathies Unit
Research in our group is focused on CharcotMarie-Tooth (CMT) neuropathies, which constitute
the most common form of human inherited neuromuscular disorders. At present, no known therapy
is available for any CMT neuropathy. CMTs are
commonly characterized by distal wasting, weakness and sensory loss, and are the consequence
of mutations in at least 70 different genes. Among
them, several CMT genes encode proteins regulating the endo-lysosomal trafficking, thus providing
the opportunity to study basic mechanisms of the
cell biology of myelination in Schwann cells, which
are largely unknown. Our laboratory contributed to
identify some of these CMT genes, whose function has been then investigated using several animal models that we generated in the last 10 years.
These models have been exploited to a) study the
natural history and progression of the disease; b) to
unravel pathogenetic mechanisms at the basis of
these neuropathies and c) to prove the efficacy of
therapeutic strategies aimed at restoring proper
myelination and favor nerve repair and regeneration. In particular, during this year:
a) we investigated the cell autonomy of FIG4
function in Schwann cells and motor neurons.
In human, recessive mutations of FIG4 are responsible for Yunis-Varón syndrome, familial
epilepsy with polymicrogyria, and CharcotMarie-Tooth type 4J neuropathy (CMT4J). Loss
of FIG4 phospholipid phosphatase causes decreased PtdIns(3,5)P2 levels and defects in
multiple pathways in the endomembrane system.
b) we assessed the role in the regulation of PNS
and CNS myelination of KIF13B motor protein
and of its interactor the DLG1 scaffold, which
we identified in Schwann cells in complex with
MTMR2, a phospholipid phosphatase mutated
in autosomal recessive demyelinating
CMT4B1.
c) we tested the hypothesis that modulation of the
NRG1 (Neuregulin) type III signaling, through the
control of its primary inhibitor TACE secretase,
could constitute an efficient treatment for hypermyelinating CMTs. This hypothesis relies on the
instructive role of NRG1 to initiate and regulate
the amount of myelination, its role in the pathogenesis of some CMT neuropathies, and its potential role in nerve repair.
Alessandra Bolino
67
DIVISION OF NEUROSCIENCE
Research Units, INSPE
Figure 13. Schwann cell/DRG neuron primary co-cultures from FIG4 knock out mouse embryos display
abnormally enlarged and vacuolated late endosomal-lysosomal compartments marked with LAMP1green (red is phalloidin)
Axo-glia interactions Unit
Myelin is a highly specialized membrane, which
wraps around axons in peripheral (PNS) and central nervous system (CNS) and is required to facilitate efficient and rapid propagation of nerve
impulses. Myelin formation is tightly regulated and
while the molecular events controlling the development of Schwann cells and oligodendrocytes
have been characterized, the axonal mechanisms
directing its production have been only recently
identified. Indeed, gliogenesis and the development of nervous system strictly depend upon interaction between neurons and glial cells. Glial cells
promote neuronal survival, regulate the organization of myelinated axons and promote axonal differentiation and myelin sheath production. Axons
promote glial cells survival and development. Alteration in myelination can have dramatic consequences ranging from reduction of the conduction
of nerve impulses to neuronal cell death, with a significant impairment of normal functionality in patients affected by demyelinating disorders.
The main interest in our laboratory is to investigate
the axonal molecules and the downstream signaling pathways intermediates they activate in myelinating glia.
In the CNS several factors contribute to myelin
sheet formation and maintenance. Unlike the PNS,
where NRG1 type III controls all the aspects linked
to myelination, in the CNS no specific factor(s) has
been identified, suggesting that axonal control of
myelination is achieved via cooperation of several
molecules. The majority of the growth factors implicated in CNS myelination are subjected to regulated processing by secretases. We recently
showed that the α-secretase ADAM17 is a key
protease controlling PNS myelination. We have
now evidences that ADAM17 promotes oligodendrocytes development and CNS myelination. In
vitro and in vivo experiments indicate that axonal
ADAM17 promotes oligodendrocytes differentiation and myelination. Further, conditional ablation
of ADAM17 in transgenic models indicates that
ADAM17 is important also in neuronal survival.
Our observations suggest the existence of posttranscriptional mechanism(s) regulating myelin formation and axonal survival and identify secretases
as a potential therapeutic target to modulate
myelination and possibly neuronal survival.
Carla Taveggia
DIVISION OF NEUROSCIENCE
Clinical Research Units, INSPE
Inflammatory CNS disorders Unit
Clinical Trials (PI: M. Rodegher). We participated in
many International RCTs (phase II, III) to evaluate
the safety and efficacy of new immunoactive
drugs in pts with MS with different disease courses. We analyzed clinical and laboratory data on
more than 1500 MS pts, treated with first-line disease modifying drugs (DMD),to identify the early
predictors of long-term disability progression. We
have carried on a prospective study to characterize clinical, MRI and Vitamin D as prognostic factors in pts at first clinical attack. Finally, we concluded a study on the prevalence of CCSVI in a
large cohort of MS pts.
Genetics of Complex Neurological Diseases (PI: F.
Martinelli-Boneschi). The laboratory was involved
in the identification of genetic risk factors and molecular mechanisms implicated in the susceptibility to complex common neurological diseases
such as MS, Alzheimer’s disease and neuropathy.
An additional activity was the identification of predictive and diagnostic, disease activity and treatment-response biomarkers involved in inflammatory and degenerative diseases. The laboratory
was also involved in the processing and bioinformatic analyses of Illumina array and sequencing
data.
Clinical Research (PI: L. Moiola). We participated
in studies evaluating the efficacy and safety of natalizumab and of different DMDs in paediatric MS.
We were involved in a project on implementation
of a web-information aid for newly diagnosed MS
pts and in a multicentre study evaluating MS patients’ risk propensity to accept risks associated
to different DMDs. We analyzed clinical, immunological and MRI data of “atypical” forms of MS,
CNS Vasculitis and of NMO. Finally, we carried
out a prospective study to evaluate safety and efficacy of long-term rituximab treatment.
Neuro-rehabilitation. We evaluated the efficacy of
different aspects of intensive multidisciplinary rehabilitation in MS pts and we concluded a study
on the identification of the predictors of disability
improvement. We were involved in studies to assess the effect of fampridine on QoL and sativex
on spasticity in progressive MS. Finally, we concluded a research aiming at evaluating the usefulness of an objective assessment of the ambulatory skills in MS outpatients using GPS technology.
Vittorio Martinelli
Cerebrovascular disorders
The cerebrovascular patient: from bedside to bench and vice versa
Epidemiological, clinical and instrumental data of
patients admitted to SU are collected in a database, and blood samples are stored. This represents an invaluable tool for clinical research and
for collaboration within national and international
networks.
Spontaneous projects:
• Study of clinical/radiological factors predictive of
haemorrhagic transformation in acute phase of
ischemic stroke.
• Identification of specific neurological deficits at
stroke onset predictive of persistent disability,
regardless the low total NIHSS.
• Study of the role of circulating monocytes in the
neurobiological processes of acute cerebral ischemia, through analysis of candidate genes
expression such as aging gene p66Shc and
plasma proteins like cytokines/chemokines.
National and international collaborations:
• IPSYS: Italian study aiming at the definition of
risk factors and genetic deteminants of young
stroke;
• MUCH-Italy: Italian study aiming at the definition
of risk factors and genetic deteminants of hemorrhagic stroke;
• CADISP: international study on whole-genome
genetic association with clinical characteristics
of pts affected by cervical arterial dissection.
Interventional trials
• OSR SU is the coordinator center of the WakeUp Stroke trial, designed to evaluate safety/efficacy of thrombolysis in pts with arousal stroke.
• IRIS: randomized vs placebo, multicentric, international, double-blind trial evaluating efficacy of
DU-176b vs warfarin in reducing the risk of
stroke in stroke pts with atrial fibrillation
69
DIVISION OF NEUROSCIENCE
Clinical Research Units, INSPE
• ENGAGE: randomized vs placebo, multicentric,
international, double-blind trial evaluating efficacy of pioglitazone in reducing the risk of stroke.
Morevoer, we have continued the optimization of
the diagnostic-therapeutic process, implementing
guidelines that involve all the staff from Emer-
gency Department to Stroke Unit and Rehabilitation. In this respect, our unit is involved in a project with the 118-Milano to better recognize and
dispatch pts for thrombolysis.
Maria Sessa
Memory disorders
In last few years the increasing of population ageing is associated with an increase of incidence of
secondary and primary forms of dementia and
our Unit is involved in some interesting studies
about these diseases. The research activity of
Memory Disorders Unit in 2013 continued the
work started during the previous years, which was
designed to improve the diagnosis at an early
stage in the various forms of dementia. Particularly in the patient with the onset of dementia in early
stage (age less than 65 years old) we decided to
make routine a series of advanced diagnostic
tests such as the dosage of cerebrospinal fluid
(CSF) biomarkers (β-amyloid, protein τ and phospho-τ), 3 Tesla brain MRI, [18F] FDG-PET brain,
that, associated with the complete neuropsychological evaluation, have allowed us to improve our
diagnostic capabilities in vivo by limiting the risk of
diagnostic errors since, as is well known, the diagnosis of certainty in different forms of dementia
is only confirmed with a post-mortem examination. The close collaboration with other research
units of our hospital (Neuroimaging Research
Unit, Functional Neuroradiology Unit, Experimental
Neurophysiology Unit, In vivo Human Molecular
and Structural Neuroimaging Unit, Laboratory of
Genetics of Complex Neurological Diseases, Proteome Biochemistry Unit) and other external centres (Negri Institute, Policlinico Hospital of Milan,
Memory and Aging Centre in San Francisco) has
enabled us to published several scientific papers
aimed at improving knowledge of the ultrastructural alterations of white and grey matter in the behavioural variant of fronto-temporal dementia
(FTD), in rare variant of FTD called Primary Progressive Aphasia and in AD. Much emphasis has
been given to projects with the clinical neurogenetic unit to improve the pharmacogenomics
knowledge: our collaboration with the Laboratory
of Genetics of our hospital also continued, in order to search for new diagnostic and pharmacogenetics markers in AD, with the collection of
DNA from AD subjects treated with Achei divided
into responders and non-responders to therapy
for the identification of genetic characteristics indicative of a better response to anticholinesterase
inhibitors therapy.
Giuseppe Magnani
Movement disorders
The Movement Disorders Unit is focused on understanding the physiopathological mechanisms
responsible for different movement disorders,
arising from both central and peripheral nervous
system dysfunctions. We are involved in the clinical and neurophysiological validation studies on
safety and efficacy of innovative therapeutic
strategies, both in clinical practice and in experimental settings. In particular we are studying several animal models of human acquired and inherited diseases in order to characterize underlying
physiopathological mechanism and to provide a
sensitive model to verify the response to experimental therapies. Further, we are committed in
the translation process of these new therapeutic
approach in human pathology, like the deep brain
stimulation in several basal ganglia disorders or
lentiviral hematopoietic stem cell gene therapy in
metachromatic leukodystrophy. Notably we are
studying the functional recovery after botulinum
toxin type A (BT-A) therapy in patients with focal
spasticity in multiple sclerosis (MS), the tuning of
the treatment of neurogenic bladder by BT-A injection into the detrusor muscle, as well as the
cortical excitability modifications in dystonic diseases. In details, we are studing the transcranial
magnetic stimulation (TMS) effect on the exteroceptive suppression (“geste antagoniste”) in cervical dystonia (CD). A peculiar finding of focal dystonia, particularly of CD is the inhibitory effect of
sensory tricks, such as touching the face or chin,
holding the nape with the hand, which were reported to decrease or even abolish dystonia in up
to 70% of the patients. Whether the inhibitory ef-
DIVISION OF NEUROSCIENCE
fect of sensory tricks is related to exteroceptive
rather than proprioceptive afferent commands is
still a matter of debate. TMS is a well-established
method for the non-invasive study of the motor
cortex. Stimulating the motor cortex with a double
magnetic stimulation over the scalp (paired-pulse
TMS, ppTMS) or with an electrical-magnetic paradigm (sensory afferent inhibition, SAI), allows to
modulate the motor output from the cortex
through intracortical as well as cortico-subcortical
network.
Ubaldo Del Carro
Neuromuscular disorders
Clinical studies in Neuromuscular Diseases are
addressed to give the best medical supports to
patients affected by neuromuscular disorders. We
are involved in several clinical studies either spontaneous or sponsored, mono-centric and multicentric, national and international.
We completed:
1. Epidemiological Study about the possible association between anti-flu vaccine and onset of
Guillain-Barrè syndrome.
We are working on:
1. A Randomized, Double-Blind, Placebo-Controlled, Multicentre Study to Assess the Efficacy on Spasticity Symptoms of a Cannabis Sativa Extract in Motor Neuron Disease Patients.
2. Evaluation of corneal confocal microscopy,
neurophysiological studies and skin biopsy in
sensory peripheral neuropathy.
3. Double blind controlled and randomized study
to evaluate the efficacy of high dose immunoglobulins in treatment of painful diabetic
polyneuropathy resistant to conventional therapy.
4. IGOS : International GBS outcome study.
5. CFTY720I2201: A double-blind, randomized,
multicenter, placebo controlled, parallel-group
study to evaluate the efficacy and safety of fingolimod 0.5 mg administered orally once daily
versus placebo in patients with chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP).
6. Functioning and quality of life in patients with
peripheral neuropathy associated with antiMAG antibodies.
7. SCIG in disimmune chronic peripheral neuropathies: a retrospective national study.
Raffaella Fazio
Paroxysmal events
Our unit is principally involved in the evaluation of
epileptic patterns and single status epilepticus
seizures. Starting from the data contained in the
database of the Center for Clinical Epilepsy, we
currently have in progress a study to identify the
clinical and neurophysiological markers indicating
the possibility of maintaining the antiepileptic therapy only for a limited number of years. Data in literature are currently generic and of little help for
the individual patient in clinical practice.
We have completed the evaluation of the neurophysiological characteristics of the experimental
model of Tuberous Sclerosis Complex in mice.
Our future program will be to assess the impact of
inflammation in the genesis and maintenance of
epilepsy. In particular, we are interested in the
evaluation of inflammatory diseases that develop
on the basis of autoimmune responses as a possible mechanism at the basis of at least a part of
the drug-resistant epilepsy.
The other side of activities involves neurophysiological studies related to vascular disease in the
acute phase. We acquired simultaneous EEG
recordings and Doppler TC in the course of thrombolytic therapy of acute ischemic stroke. The work
program includes an evaluation of the actual feasibility of these systems of monitoring during both
their real clinical utility in the description of the procedure performance and the ability to provide data
of short-and long-term prognosis already in the
acute phase of the treatment.
Fabio Minicucci
71
DIVISION OF NEUROSCIENCE
Selected publications
Cozzi, A; Santambrogio, P; Privitera, D; Broccoli, V; Rotundo, LI; Garavaglia, B; Benz, R; Altamura, S; Goede, JS; Muckenthaler, MU and Levi, S. Human L-ferritin deficiency is characterized by
idiopathic generalized seizures and atypical restless leg syndrome. J. Exp. Med.: 2013; 210(9):
1779-1791 - Article
IF 2012: 13,214
Laterza, C; Merlini, A; De Feo, D; Ruffini, F; Menon, R; Onorati, M; Fredrickx, E; Muzio, L;
Lombardo, A; Comi, G; Quattrini, A; Taveggia, C; Farina, C; Cattaneo, E and Martino, G. iPSCderived neural precursors exert a neuroprotective role in immune-mediated demyelination via the secretion of LIF. Nat. Commun.: 2013; 4: 2597 - Article
IF 2012: 10,015
Benedetti, F; Bollettini, I; Barberi, I; Radaelli, D; Poletti, S; Locatelli, C; Pirovano, A; Lorenzi, C;
Falini, A; Colombo, C; Smeraldi, E. Lithium and GSK3-β promoter gene variants influence white
matter microstructure in bipolar disorder. Neuropsychopharmacology: 2013; 38(2): 313-327 - Article
IF 2012: 8,678
Agosta, F; Sala, S; Valsasina, P; Meani, A; Canu, E; Magnani, G; Cappa, SF; Scola, E; Quatto,
P; Horsfield, MA; Falini, A; Comi, G; Filippi, M. Brain network connectivity assessed using graph
theory in frontotemporal dementia. Neurology: 2013; 81(2): 134-143 - Article
IF 2012: 8,249
Filippi, M; Preziosa, P; Copetti, M; Riccitelli, G; Horsfield, MA; Martinelli, V; Comi, G; Rocca,
MA. Gray matter damage predicts the accumulation of disability 13 years later in MS. Neurology:
2013; 81(20): 1759-1767 - Article
IF 2012: 8,249
Colombo, E; Bedogni, F; Lorenzetti, I; Landsberger, N; Previtali, SC; Farina, C. Autocrine and
immune cell-derived BDNF in human skeletal muscle: Implications for myogenesis and tissue regeneration. J. Pathol.: 2013; 231(2): 190-198 - Article
IF 2012: 7,585
Canessa, N; Crespi, C; Motterlini, M; Baud-Bovy, G; Chierchia, G; Pantaleo, G; Tettamanti,
M; Cappa, SF. The functional and structural neural basis of individual differences in loss aversion. J.
Neurosci.: 2013; 33(36): 14307-14317 - Article
IF 2012: 6,908
Noseda, R; Belin, S; Piguet, F; Vaccari, I; Scarlino, S; Brambilla, P; Martinelli-Boneschi, F;
Feltri, ML; Wrabetz, L; Quattrini, A; Feinstein, E; Huganir, RL; Bolino, A. DDIT4/REDD1/RTP801 is
a novel negative regulator of schwann cell myelination. J. Neurosci.: 2013; 33(38): 15295-15305 Article
IF 2012: 6,908
Martinelli-Boneschi, F; Giacalone, G; Magnani, G; Biella, G; Coppi, E; Santangelo, R; Brambilla, P; Esposito, F; Lupoli, S; Clerici, F; Benussi, L; Ghidoni, R; Galimberti, D; Squitti, R; Confaloni,
A; Bruno, G; Pichler, S; Mayhaus, M; Riemenschneider, M; Mariani, C; Comi, G; Scarpini, E; Binetti, G; Forloni, G; Franceschi, M; Albani, D. Pharmacogenomics in Alzheimer’s disease: A genomewide association study of response to cholinesterase inhibitors. Neurobiol. Aging: 2013; 34(6):
1711.e7-1711.e13 - Article
IF 2012: 6,166
Consonni, M; Cafiero, R; Marin, D; Tettamanti, M; Iadanza, A; Fabbro, F; Perani, D. Neural convergence for language comprehension and grammatical class production in highly proficient bilinguals is independent of age of acquisition. Cortex: 2013; 49(5): 1252-1258 - Article
IF 2012: 6,161
Filippi, M; Agosta, F; Scola, E; Canu, E; Magnani, G; Marcone, A; Valsasina, P; Caso, F;
Copetti, M; Comi, G; Cappa, SF; Falini, A. Functional network connectivity in the behavioral variant
of frontotemporal dementia. Cortex: 2013; 49(9): 2389-2401 - Article
IF 2012: 6,161
Amato, N; Riva, N; Cursi, M; Martins-Silva, A; Martinelli, V; Comola, M; Fazio, R; Comi, G;
Leocani, L. Different Frontal Involvement in ALS and PLS Revealed by Stroop Event-Related Potentials and Reaction Times. Front. Aging Neurosci.: 2013; 5: 82 - Article
DIVISION OF NEUROSCIENCE
IF 2012: 5,224
Pelizzoni, I; Zacchetti, D; Campanella, A; Grohovaz, F; Codazzi, F. Iron uptake in quiescent and
inflammation-activated astrocytes: a potentially neuroprotective control of iron burden. Biochim. Biophys. Acta Mol. Basis Dis.: 2013; 1832(8): 1326-1333 - Article
IF 2012: 4,910
Tagliavacca, L; Colombo, F; Racchetti, G; Meldolesi, J. L1CAM and its cell-surface mutants:
New mechanisms and effects relevant to the physiology and pathology of neural cells. J. Neurochem.: 2013; 124(3): 397-409 - Article
IF 2012: 3,973
Losa, M; Donofrio, CA; Barzaghi, R; Mortini, P. Presentation and surgical results of incidentally
discovered nonfunctioning pituitary adenomas: Evidence for a better outcome independently of other patients’ characteristics. Eur. J. Endocrinol.: 2013; 169(6): 735-742 - Article
IF 2012: 3,136
Selected publications, INSPE
Filippi, M; Preziosa, P; Copetti, M; Riccitelli, G; Horsfield, MA; Martinelli, V; Comi, G; Rocca,
MA. Gray matter damage predicts the accumulation of disability 13 years later in MS. Neurology:
2013; 81(20): 1759-1767 - Article
IF 2012: 8,249
Colombo, E; Bedogni, F; Lorenzetti, I; Landsberger, N; Previtali, SC; Farina, C. Autocrine and
immune cell-derived BDNF in human skeletal muscle: Implications for myogenesis and tissue regeneration. J. Pathol.: 2013; 231(2): 190-198 - Article
IF 2012: 7,585
Noseda, R; Belin, S; Piguet, F; Vaccari, I; Scarlino, S; Brambilla, P; Martinelli-Boneschi, F;
Feltri, ML; Wrabetz, L; Quattrini, A; Feinstein, E; Huganir, RL; Bolino, A. DDIT4/REDD1/RTP801 is
a novel negative regulator of schwann cell myelination. J. Neurosci.: 2013; 33(38): 15295-15305 Article
IF 2012: 6,908
Martinelli-Boneschi, F; Giacalone, G; Magnani, G; Biella, G; Coppi, E; Santangelo, R; Brambilla, P; Esposito, F; Lupoli, S; Clerici, F; Benussi, L; Ghidoni, R; Galimberti, D; Squitti, R; Confaloni,
A; Bruno, G; Pichler, S; Mayhaus, M; Riemenschneider, M; Mariani, C; Comi, G; Scarpini, E; Binetti, G; Forloni, G; Franceschi, M; Albani, D. Pharmacogenomics in Alzheimer’s disease: A genomewide association study of response to cholinesterase inhibitors. Neurobiol. Aging: 2013; 34(6):
1711.e7-1711.e13 - Article
IF 2012: 6,166
Peruzzotti-Jametti, L and Cambiaghi, M; Bacigaluppi, M; Gallizioli, M; Gaude, E; Mari, S;
Sandrone, S; Cursi, M; Teneud, L; Comi, G; Musco, G; Martino, G and Leocani, L. Safety and
efficacy of transcranial direct current stimulation in acute experimental ischemic stroke. Stroke:
2013; 44(11): 3166-3174 - Article
IF 2012: 6,158
73
DIVISION OF NEUROSCIENCE
Research Units
Cellular neurophysiology Unit
Developmental neurogenetics Unit
DIVISION OF NEUROSCIENCE
Neuropsychopharmacology Unit
Molecular genetics of mental retardation Unit
75
DIVISION OF NEUROSCIENCE
Proteomics of iron metabolism Unit
Clinical neuroimmunology
DIVISION OF NEUROSCIENCE
Immunobiology of neurological disorders
Memory disorders
77
DIVISION OF NEUROSCIENCE
Neuromuscular repair
Axo-glia interactions Unit
DIVISION OF NEUROSCIENCE
Human inherited neuropathies Unit
Neuroimmunology Unit
79
DIVISION
OF
METABOLIC AND
CARDIOVASCULAR SCIENCES
Scientific Coordinator:
Zaverio M. Ruggeri
Associate Directors:
Ottavio Alfieri*, Emanuele Bosi*
Research Units
Coagulation and platelet biology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––– 86
HEAD OF UNIT: Zaverio M. Ruggeri
RESEARCHER: Chiara Foglieni
FELLOWS: Maria Lombardi, Maria Elena Mantione
Type 2 diabetes and diabetic complications –––––––––––––––––––––––––––––––––––––––––––– 87
HEAD OF UNIT: Emanuele Bosi*
Cardiodiabetes & core Lab
GROUP LEADER: Lucilla D. Monti
POST-DOCTORAL FELLOW: Elena Galluccio
FELLOW: Serena Spadoni
TECHNICIANS: Sabrina Costa, Barbara Fontana
Complications of diabetes ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 87
GROUP LEADER: Gianpaolo Zerbini
POST-DOCTORAL FELLOW: Silvia Maestroni
FELLOWS: Valentina Martina, Alice Spinello
CONSULTANT: Mara Lorenzi
TECHNICIAN: Daniela Gabellini
Metabolism, nutrigenomics and cell differentiation ––––––––––––––––––––––––––– 88
GROUP LEADER: Ileana Terruzzi
POST-DOCTORAL FELLOW: Nausicaa Mazzocchi
81
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Research Units / Clinical Research Units
Bone metabolism Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 89
HEAD OF UNIT: Alessandro Rubinacci
RESEARCHER: Isabella Villa
POST-DOCTORAL FELLOW: Simona Bolamperti
FELLOW: Alice Spinello
CONSULTANTS: Giovanna Mignogna, Gianluigi Moro, Marcella Sirtori
TECHNICIAN: Rita Masullo
Coagulation service & thrombosis research Unit –––––––––––––––––––––––––––––––––––––– 89
HEAD OF UNIT: Armando D’Angelo*
RESEARCHERS: Patrizia Della Valle, Annalisa Fattorini
PHYSICIANS: Luciano Crippa, Silvana Viganò
TECHNICIAN: Francesca Sampietro
Pediatric endocrinology research –––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 90
HEAD OF UNIT: Giuseppe Chiumello*
GROUP LEADER: Stefano Mora
FELLOWS: Silvia Capelli, Cecilia Diceglie, Katia Maruka, Ilaria Zamproni
TECHNICIAN: Maria Puzzovio
Clinical Research Units
Diabetes and endocrinology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 91
HEAD OF UNIT: Emanuele Bosi*
PHYSICIANS: Alberto Davalli, Gabriella Galimberti, Roberto Lanzi, Marco Federico Manzoni,
Matteo Rocco Pastore, Alessandro Saibene, Maurizio Storti
RESIDENTS: Andrea Bolla**, Amelia Caretto**, Anna Dolcetta Capuzzo, Ilaria Formenti**,
Laura Frosio**, Alessandra Gandolfi**, Tania Garito**, Chiara Molinari**, Valentina Villa**
FELLOWS: Raffaele Di Fenza, Andrea Laurenzi, Alessandro Rossini
NUTRITIONIST: Monica Marchi
Cardio-metabolism and clinical trials –––––––––––––––––––––––––––––––––––––––––––––– 91
CLINICAL GROUP LEADER: Piermarco Piatti
FELLOWS: Valentina Giulia Crippa, Francesca Perticone, Emanuela Setola
RESEARCH NURSE: Michela Stuccillo
Fetal-maternal medicine ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 92
HEAD OF UNIT: Massimo Candiani*
CLINICAL GROUP LEADER: Maria Teresa Castiglioni
RESEARCHERS: Paolo Cavoretto, Susanna Rosa, Maddalena Smid, Luca Valsecchi
FELLOWS: Lara Di Piazza, Annalisa Inversetti, Federica Pasi
Pediatrics Unit
HEAD OF UNIT: Giuseppe Chiumello*
Clinical pediatric endocrinology –––––––––––––––––––––––––––––––––––––––––––––––––––– 92
CLINICAL GROUP LEADER: Giovanna Weber*
RESEARCHERS: Gisella Garbetta, Sara Osimani, Gabriella Pozzobon, Gianni Russo,
Maria Cristina Vigone
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Clinical Research Units
RESIDENTS: Silvana Caiulo**, Chiara Damia**, Marianna Di Frenna**, Alessandra Di
Lascio**, Valentina Donghi**, Maria Piera Ferrarello**, Moira Gianninoto**, Silvia
Meroni**, Elena Peroni**, Sarah Rabbiosi**, Giulia Maria Tronconi**
Diabetes and metabolic diseases in children and adolescents –––––––––––––– 93
CLINICAL GROUP LEADER: Franco Meschi
RESEARCHERS: Stefania Di Candia, Andrea Rigamonti, Paola Sgaramella
Neonatology ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 93
CLINICAL GROUP LEADER: Graziano Barera
RESEARCHERS: Gisella Garbetta, Antonella Poloniato, Rosanna Rovelli
Structural heart disease Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 94
HEAD OF UNIT: Ottavio Alfieri*
PHYSICIANS: Stefano Benussi, Michele De Bonis, Francesco Maisano
FELLOWS: Andrea Guidotti, Davide Schiavi
Cardiopulmonary clinical physiology Unit –––––––––––––––––––––––––––––––––––––––––––––––– 95
HEAD OF UNIT: George Cremona
RESIDENTS: Barbara Calcaterra, Sara Dal Farra, Anna Chiara Ogliari
CONSULTANT: Gabriella Gambaro
TECHNICIAN: Antonella Fumagalli
Cardiovascular interventions Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 95
HEAD OF UNIT: Antonio Colombo
PHYSICIANS: Mauro Carlino, Alfredo Castelli, Alaide Chieffo, Filippo Figini, Azeem Mohamed
Latib, Matteo Montorfano
FELLOWS: Chiara Bernelli, Jaclyn Chi Lin Chan, Georgina Fuertes, Gennaro Giustino,
Caroline J. Magri, Tadashi Miyazaki, Toru Naganuma, Charbel A. Naim, Vasilis
Panoulas, Katsumasa Sato, Paola Spatuzza
TRIAL COORDINATOR: Angela Ferrari
Center for arrhythmia research –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 96
HEAD OF UNIT: Paolo Della Bella
PHYSICIANS: Francesca Baratto, Caterina Bisceglia, Simone Gulletta, Giuseppe Maccabelli,
Patrizio Mazzone, Gabriele Paglino, Andrea Radinovic, Simone Sala, Nicola Trevisi,
Pasquale Vergara
Echocardiography Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 96
HEAD OF UNIT: Giovanni La Canna
PHYSICIANS: Emanuela Alati, Giovanna Di Giannuario
FELLOW: Chiara Sordelli
TECHNICIAN: Marta Martino
Ischaemic heart disease, heart failure and echocardiography Unit –––––––––––––––– 97
HEAD OF UNIT: Alberto Margonato*
PHYSICIANS: Eustachio Agricola, Alberto Capelletti, Gabriele Fragasso, Michele Oppizzi,
Cristina Pedrigi
RESIDENT: Claudia Montanaro **
83
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Clinical Research Units
Organ protection in critically ill patients, Advanced cardiac –––––––––––––––––––––––– 98
failure and mechanical supports Unit
HEAD OF UNIT: Alberto Zangrillo*
PHYSICIANS: Pier Carlo Bergonzi, Tiziana Bove, Luca Cabrini, Maria Grazia Calabrò, Remo
Daniel Covello, Antonella Crescenti, Martina Crivellari, Annalisa Franco, Chiara Gerli,
Giovanni Landoni*, Carlo Leggieri, Giulia Maj, Daniela Mamo, Giulio Melisurgo, Fabrizio
Monaco, Giacomo Monti, Federico Pappalardo, Anna Mara Scandroglio, Massimo
Zambon
POST-DOCTORAL FELLOWS: Francesca Isella, Diana Taddeo
RESIDENTS: Giovanni Borghi, Andrea Montisci, Marina Pieri, Laura Ruggeri, Valentina Testa
FELLOWS: Alessandro Belletti**, Alessandro Putzu**, Omar Saleh**, Dario Winterton**
QUALITY ASSURANCE AND REGULATORY AFFAIRS: Rosalba Lembo, Simona Massani,
Lara Sussani, Paola Zuppelli
Strategic research on heart failure Unit –––––––––––––––––––––––––––––––––––––––––––––––––– 99
HEAD OF UNIT: Paolo Camici*
PHYSICIANS: Enrico Ammirati, Marco Magnoni, Roberto Spoladore**
POST-DOCTORAL FELLOWS: Massimiliano Mancini**, Paolo Musarò, Angela Scavone**
RESIDENTS: Alessandro Durante**, Alessia Faccini**, Alessandra Laricchia, Francesco
Maranta**, Damiano Regazzoli**
FELLOWS: Rocco Baccaro, Veronica Buia, Ilaria My, Isabella Scotti, Valentina Turco
Study and treatment of aortic disease Unit –––––––––––––––––––––––––––––––––––––––––––––– 99
HEAD OF UNIT: Roberto Chiesa*
PHYSICIANS: Domenico Astore, Renata Clotilde Castellano, Efrem Civilini, Laura Dordoni,
Gloria Esposito, Enrico Maria Marone, Massimiliano Marrocco-Trischitta, Germano
Melissano*, Yamume Tshomba
RESIDENTS: Luca Apruzzi **, Serena Frezza**, Jessica Lanza, Davide Logaldo, Daniele
Mascia **, Girolomina Mazzeo, Enrico Rinaldi **, Sara Spelta, Renato Vitale**
FELLOWS: Domenico Baccellieri, Luca Bertoglio, Chiara Brioschi, Andrea Kahlberg
Vision first Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 100
HEAD OF UNIT: Francesco Bandello*
PHYSICIANS: Nicola Baccelli, Piero Barboni, Maurizio Battaglia Parodi, Paolo Bettin, Loredana
Bonisolli, Elena Bruschi, Raffaele Di Fenza**, Maria Lucia Cascavilla, Carlo Ciampi, Marco
Codenotti, Umberto De Benedetto, Federico Di Matteo, Marina Fiori, Maddalena Forti,
Marco Gagliardi, Matteo Ghidoni (until March 2013), Silvia Giatsidis, Antonio Giordano
Resti, Lauretta Guarisco, Ugo Introini, Rosangela Lattanzio, Francesca Legorini, Francesco
Loperfido, Gisella Maestranzi, Angela Malegori, Maria Pia Manitto, Elisabetta Martina, Paolo
Mauceri, Elisabetta Miserocchi, Giulio Modorati, Veronica Odazio, Luisa Pierro, Matteo
Prati, Giuseppe Querques, Andrea Ramoni, Carmen Rojo, Alessandra Spinelli, Monica
Stoppani, Alessandra Tavola, Ilaria Zucchiatti
RESIDENTS: Luigi Berchicci**, Ingrid Bianchi**, Giuseppe Casalino**, Giulia Corradetti**,
Claudia Del Turco**, Giovanni Fogliato**, Lorenzo Iuliano**, Karl Anders Knutsson**, Carlo
La Spina**, Jacopo Milesi**, Davide Panico**, Lea Querques**, Giacinto Triolo**
TECHNICIANS: Giorgio Alto, Adriana Angiolini, Alessio Buzzotta, Silvia Giganti (until March
2013), Silvia Marcaggi (from June 2013), Antonella Ribecca
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Introduction by the Directors
Mission and Vision - It is unquestionable that some of the most relevant diseases with high social, economic and clinical impact in developed societies link disorders of metabolism to chronic and acute alterations of cardiovascular function. Metabolic and cardiovascular diseases represent a major area of
clinical care and research at San Raffaele Research Institute. Thus, the Division of Metabolic and Cardiovascular Sciences is devoted to planning an integrated approach to treat patients and understand
mechanisms based on a structured view of the pathophysiological connections between metabolic and
cardiovascular alterations. Such a vision could set a strong example of how to tackle complex problems
with beneficial outcomes.
Aim of the Division is therefore not only to exploit the obvious possibility of synergy at the level of basic
research, but also the creation of clinical programs in which experts in the study of altered metabolism
are integrated in the team of cardiologists, cardiac surgeons, vascular surgeons and cardiac emergency
physicians treating acute or chronic cardiovascular diseases. Conversely, cardiovascular specialists should
be part of the clinical team evaluating and treating patients with metabolic disorders.
Goals - The biology of endothelium may be considered as a theme of unifying interest and particular relevance to research bridging the metabolic and cardiovascular disease areas. This could easily be expanded to include the biology of other cellular components of the vessel wall – smooth muscle cells,
fibroblasts, inflammatory cells and adipocytes – which play a concerted and fundamental role in controlling all responses to acute and chronic vascular injuries. Along with this unifying theme, areas of interest
span from the mechanisms of myocardial damage; thrombosis; hemostatic imbalance (post-surgery
bleeding in emergency patients and patients with ventricular assisting devices); pathobiology of the atherosclerotic plaque; metabolic alterations leading to cardiovascular diseases, in particular insulin resistance and type 2 diabetes; material sciences and bioengineering with respect to developing new devices;
and cell therapies. The outcomes of this integrated approach will lay new grounds for innovative treatments
of established metabolic and cardiovascular diseases, personalized preventive medicine programs and
new generations of clinical and nutritional studies.
Achievements - Work performed in the Division is internationally recognized in several areas of excellence
including arrhythmology, cardiac valve and aortic surgery, acute and chronic myocardial damage, coronary revascularization, vascular inflammation, insulin resistance, diabetes and diabetic macro- and microangiopathy, intermediary and energy metabolism, bone pathophysiology.
Training Opportunities - The Division, through the intertwined connections with several Clinical Care Departments, gives ample support to the Postgraduate Schools in Anesthesia and Intensive Care, Cardiovascular Diseases, Cardiac Surgery, Vascular Surgery, Endocrinology and Metabolic Diseases, Obstetrics
and Gynecology, Pediatrics, and Ophthalmology.
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DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Research Units
Coagulation and platelet biology Unit
Activity of the Coagulation and Platelet Biology Unit
has been limited to the group coordinated by Dr.
Chiara Foglieni owing to the lack of dedicated facilities. According to a reorganization implemented
by the Scientific Direction, only this group will remain operative after 2013. The Foglieni laboratory
focuses on the molecular and cellular vascular
components responsible for atherosclerotic plaque
destabilization and the onset of arterial thrombosis.
These studies involve the Vascular Surgery Unit
(prof. R. Chiesa) and the Structural Heart Disease
Unit (prof. O. Alfieri). Platelet aggregates and fibrin
resulting from coagulation activation are key components of the thrombi that occlude arteries. Thus,
cellular and molecular components of the atherosclerotic vessel might participate in the development and progression of atherothrombosis by
directly or indirectly interacting with platelets and/or
mediators of coagulation. We have optimized
human vessels tissue and primary human smooth
muscle cells culture models, and developed meth-
ods for the analysis of P2X7 and MMP9 suitable
for functional studies of the pathogenesis of atherosclerosis and atherothrombosis. Our findings are
highlighting distinct thrombogenic roles of the vascular layers, depending on the degree and type of
alteration, as well as new synergistic functions of
tissue factor and coagulation contact phase pathways in thrombus formation. We are also collaborating with Dr. F. Canducci (Insubria University),
Prof. R. Burioni and Prof. M. Clementi (Vita-Salute
San Raffaele University), and Dr. A. Rubinacci
(Bone metabolism Unit) to study the molecular immune response in experimental atherosclerosis.
Collaborative relationships have been established
also with Dr. G. Fragasso and Prof. A. Margonato
(Heart Failure Clinic-Clinical Cardiology) to investigate heart failure mechanisms. We anticipate obtaining results that will help improve diagnosis and
treatment of atherothrombotic disorders.
Zaverio M. Ruggeri
Figure 14. Structural and functional analysis of atherosclerotic carotid artery tissue cultured after explant. a) Atherosclerotic
macro-sections for tissue culture dissected from a carotid artery specimen obtained by endarterectomy. b) Histological
examination of the carotid artery sections after 30 min (t 0), 3, 7, 10 and 15 days of culture displaying morphology
preservation over time. c) Visualization and quantification by real-time confocal videomicroscopy of platelet aggregates
and fibrin strands formed over carotid artery cryosections following blood perfusion; note the comparable response of
specimens after 30 min (t 0) and 3 days (t 3) of culture, but the different response of the diverse vascular wall layers. d)
Confocal microscopy characterization of smooth muscle cells explanted from atherosclerotic carotid artery fragments and
analysis of their response to P2X7 specific antagonists (A740003, KN62) and to the physiologic agonist, ATP.
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Cardiodiabetes & core Lab
Translational studies on gene polymorphysms and type 2 diabetes and
cardiovascular disease
Our group demonstrated a phenotype characterized by increased fasting nitric oxide levels but reduced response after an insulin stimulus. Further,
we found a strong association between eNOS
gene variants and T2DM and CAD. The polymorphism in intron 19 of eNOS affects mRNA maturation, hence yielding a consistent skipping of exons
20 and 21. This generates a stable truncated form
of eNOS that exerts a dominant negative effect.
These stable eNOS isoforms with altered properties
were present in platelets and endothelial cells with
a characteristic pro-atherogenic phenotype and alteration of vascular function in healthy subjects
mutated for eNOS gene variants. The proposed
mechanism provides a suggestive explanation for
the increase of early restenosis in mutated CAD patients. The negative contribution of these mutation
both in term of mortality or in term of early restenosis in subjects with eNOS variants were associated
with increased risk of restenosis/amputation after
PTA in patients with limb ischemia. Moreover, these
patients showed significantly lower circulating
EPCs. The pharmacogenetics analysis of the pres-
ent study showed that the best effect in stimulating
EPCs and in turn reducing restenosis was found in
patients not presenting eNOS variants and treated
by Intensified Insulin treatment. Recent data seems
to demonstrate, in healthy subjects, that eNOS
gene variants correlate with a reduced number of
EPCs. While these data open to new intriguing
perspectives in viewing different diseases involving
vasculature response to NO, further studies are
needed to clarify the molecular mechanisms of action and regulation of truncated eNOS protein both
in CAD patients and in mutated healthy subjects, a
new potential class at risk for early atherosclerosis
and glucose intolerance (GI). In fact, in a large cohort of FDR healthy subjects, we found that eNOS
gene mutation associates with GI, suggesting an increased susceptibility for these patients to become
diabetic. An international patent was posted
(PCT/EP2011/068471, number WO2012052555)
on the beneficial effects of a bar with a low content
in sugars and proteins but added with L-arginine.
Lucilla D. Monti
Complications of diabetes
Prevention of the microvascular complications of diabetes: new
approaches
The only feasible way to prevent the microvascular
complications of diabetes is to start the specific
preventive treatment as soon as possible after the
onset of diabetes, when irreversible, glucose-induced abnormalities, are still not present.
Diabetic retinopathy. To find a way to prevent this
complication during the last year we used a double strategy: a) early identification of the patients at
risk to develop the complication and b) setting up
of new preventive pharmacologic approaches. a) In
this field we have demonstrated that an increased
activity of circulating endothelial progenitor cells
(cells originated from the bone marrow with the
aim to maintain the turnover of mature endothelial
cells) characterizes the patients at risk to develop
the complication and that a similar dysfunction predicts also the development of a disease closely related to diabetic retinopathy, i.e. age-related macular degeneration, thus further validating the role of
the biomarker. b) Based on recent evidences suggesting that the first component of the retina affected by glucotoxicity is the neuroretina, we have
set up a study (presently ongoing), aimed to verify
the effect of early neuroprotection on the pathogenesis of diabetic retinopathy in a mouse model
of type 1 diabetes.
Diabetic nephropathy. The progression of this complication is characterized by the gradual decrease
of the number of intraglomerular podocytes (the
cells in charge of the size-selectivity of the glomerular filtration), paralleled by an increased urinary excretion of these same cells, suggesting a direct role
of podocyturia in the progression of the disease.
During the last year we have demonstrated that
podocyturia is characterized by the presence of a
large number of immature podocytes suggesting
that glucose might directly induce the dedifferentiation of resident podocytes with consequent detachment from the basement membrane. We are
now involved in a new study aimed to verify
whether, by inhibiting the process of in vivo dedifferentiation it is also possible to reduce the number
of immature podocytes excreted with urine.
Gianpaolo Zerbini
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DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Research Units
Metabolism, nutrigenomics and cell differentiation
Nutrigenomics is the aspect of our research interested in understanding the molecular-level interaction between nutrients and genome. This area
is organized in translational projects following our
identification of specific natural substances with
insulin-mimetic effects.
Among these, conglutin γ study has led to a
patent deposition recognizing its insulin-mimetic
properties, providing a possible nutraceutical/
pharmaceutical development of a food compound to prevent and treat insulin resistance and
related diseases.
Because insulin anabolic effect, we are studying
the cellular action of natural molecules as resveratrol and betaine on skeletal muscle metabolism,
differentiation and hypertrophy. Our published results show that these molecules might regulate
cell cycle and promote muscle differentiation and
myotubes size: Betaine supplement enhances
skeletal muscle differentiation in murine myoblasts
via IGF-1 signaling activation; RSV regulates cell
cycle exit, induces C2C12 muscle differentiation
and might control MRFs and muscle-specific pro-
teins synthesis. In addition, RSV stimulates IGF-1
signaling pathway, in particular AKT and ERK 1/2
protein activation, AMPK protein level and induces hypertrophic morphological changes in
neo-formed myotubes modulating cytoskeletal
proteins expression. indicating a possible new
drug/integrator strategy in sport performance and
clinical conditions characterized by muscle impairment. Currently, an aim of our resaearch project is
to assess the ability of RSV to preserve muscle,
fat and liver function in relation to glucose metabolism in mice subjected to a high fat diet (HFD).
Another aspect of our research is the study the
effects of these substances on primary skeletal
muscle cultures/skeletal muscle biopsies from
patients with muscle diseases. Both patients with
type 2 diabetes (T2DM) and myotonic dystrophy
(MD) show insulin resistance and skeletal muscle
damage. This project aims to investigate the possible relationship between defects in insulin signalling and muscle atrophy and the effects of insulin mimetic natural compounds
Ileana Terruzzi
Figure 15. Resveratrol (0,1 and 25 μM) action on MyHC and p21 expression, myotubes morphology,
nuclei arrangement in hypertrophy at the end of differentiation process. Immunofluorescence analysis
shows hypertrophic morphological changes in MyHC-positive neo-formed myotubes after RSV treatment. Scale bar 50 μm. p21 Immunofluorescence images and DAPI also confirms the nuclei arrangement in neo-formed myotubes after RSV treatments in respect to DM condition. Scale bar 50 μm. In:
Montesano A, Luzi L, Senesi P, Mazzocchi N, Terruzzi I Resveratrol promotes myogenesis and hypertrophy in murine myoblasts. J Transl Med. 2013 Dec 13;11:310 doi: 10.1186/1479-5876-11-310.
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Bone metabolism Unit
The Bone Metabolism Unit is actually engaged in
two major study lines:
One line is focused on the biomolecular signalings and the endocrine milieu that characterize femural fracture: a major public health treat representing the most devastating outcome of osteoporosis. The study attempts to characterize
genes expression in bone tissue as well as the
miRNAs presence in both bone and serum of osteoarthritic and fractured patients admitted to our
Orthopaedic Unit with the ultimate aim to define
the potential value of serum miRNAs as biomarkers of bone diseases state, in particular of the osteoporosis severity state (i.e femural fracture vs
primary osteoarthritis). Preliminary results have
identified an OPG/RANKL ratio promoting osteoclastogenesis and a disregulation of the Wnt signaling.
The other study line is focused on the physiological role of the osteocyte- lining cells syncitium
with the aim to understand its contribution to the
mechanisms underlying plasma calcium homeostasis, mechano-transduction and targetted re-
modelling which are all potentially affected by aging, microgravity and renal insufficiency. This
study is done through collaborative studies with
the Endocrine Unit, Harvard, Boston, and it has
been recently inserted in the Joint Universities
Summer Teaching Laboratory (JUSTL) program at
the Marine Biological Laboratory (MBL) in Woods
Hole, Massachusetts, USA. Animals lacking
PTH/PTHrp receptor (PTH1R) expression in osteocytes (OcyPTHR1-KO), developed at Harvard,
and littermate controls are used to investigate calcium efflux and influx from bone using a scanning
ion-selective electrode technique (SIET). Preliminary results have outlined the role of PTH.
The Bone Metabolism Unit is also engaged in collaborative studies with IRCCS Istituto Ortopedico
Galeazzi, Milano, Italy for the evaluation of calcium
metabolism in fish scales and with the Department of Molecular Medicine, Section of Biochemistry, University of Pavia, Italy for the evaluation of
the impaired osteoblastogenesis in murine models of osteogenesis imperfecta.
Alessandro Rubinacci
Coagulation service & thrombosis research Unit
Our Unit is currently involved in the extensive
analysis of the thrombin generation test (TGT), in
the attempt to mirror the clotting potential within
the microcirculation. As opposed to the routine
PT and aPTT tests, the TGT makes use of a low
tissue factor concentration (TF, 1 to 5 pmol),
which permits analysis of the amplification/propagation phase of the clotting process. This renders
the test sensitive to defects of the intrinsic coagulation pathway while triggering the physiological
hemostatic response via the FVIIa/TF complex. To
insure comparability of the results we have shown
that reference to the normal pooled plasma’s
thrombogram is mandatory, and we have also
identified numerical parameters which may independently better describe the clotting status of
the test plasma (lag-time ratio, peak velocity ratio,
acceleration ratio, true-tail ratio, endogenous
thrombin potential ratio, with ratios >1.0 indicating
hypercoagulability versus normal pooled plasma).
To mimic the setting of microcirculation, we have
identified optimal conditions to detect defects in
natural anticoagulant systems (protein C, antithrombin) by the addition of selected concentration of thrombomodulin (protein C system) and
fondaparinux (which selectively activates the FXa
neutralizing activity of antithrombin). Finally, we
have also developed a software which permits
the graphical representation of the test plasma’s
thrombogram as percentage values – positive or
negative - of the normal pooled plasma’s thrombogram. By analysis of apparently healthy volunteers and patients with established thrombophilia
markers (FV Leiden, prothrombin mutation, protein C, protein S and antithrombin deficiencies, or
combinations) we show the potential of the modified TGT to identify patients with hypercoagulability inspite of the absence of established thrombophilia markers. Patients on anti-vitamin K drugs
may experience major bleeding or thrombosis
episodes while on therapeutic INR values. We
show that our modification of the TGT has also
the potential to identifiy patients who are either hypercoagulable or excessively anticoagulated inspite of therapeutic INR values. The modified TGT
may alsoidentify patients with severe sepsis/septic shock requiring antithrombin and/or protein C
supplementation.
Armando D’Angelo
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DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Research Units
Pediatric endocrinology research
Our group, in collaboration with the Universities of
Milan, Insubria, and Catania, is participating in a
study aimed to the identification of genetic markers of Congenital Hyperinsulinism of Infancy (HI,) a
rare disorder of glucose metabolism. We established a National Registry for this disease, and we
enrolled and studied over 40 families with HI. Molecular studies lead to the identification of several
novel mutations responsible for the disease.
We are also actively involved in the study of bone
health in several pediatric disorders. Osteoporosis
is regarded as a condition of the elderly, but it is
now clear that it has its antecedents during childhood and adolescence. A major role in the development of osteoporosis is the bone mass gain
occurring during growth. The concerted action of
bone-forming cells (osteoblasts), and bone resorbing cells (osteoclasts) is crucial for the development of a healthy and competent skeleton. Although genetic factors play a crucial role in the
determination of bone mass gain, bone metabolism impairment during childhood and adolescence leads to a deficient skeletal development
We are investigating the role of antiretroviral treatment on bone mass in HIV-infected youths, in collaboration with Vania Giacomet and Gian Vincenzo Zuccotti at L. Sacco Hospital in Milan. We are
also studying bone mass and bone metabolism in
young patients with congenital adrenal hyperplasia, a disease leading to disturbances of sexual
differentiation. Hypophosphatemic rickets is a rare
condition leading to impaired bone mineralization,
skeletal deformities, and metabolic disturbances.
The cause of the disease have been described
recently, but they remain unknown in some patients. Our group is involved in a collaborative
study with the group of Maria Luisa Brandi, University of Florence, to identify the genetic causes
of this type of rickets.
Stefano Mora
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Clinical Research Units
Diabetes and endocrinology Unit
Prevention and new therapies of type 2 diabetes.
This line of investigation is pursued within the Cardio-Diabetes and Clinical Trials Unit. A recent accomplishment is the demonstration of improvement of glucose metabolism, insulin sensitivity, insulin secretion and endothelial function in subjects with impaired glucose tolerance and metabolic syndrome by a nutritional approach based
on L-Arginine-enriched biscuits with low sugar
and protein content. This study opens innovative
avenues for the prevention of type 2 diabetes by
non pharmacological approaches. Moreover, a
large number of phase III and some phase II clinical trials are being conducted, with more than
400 patients on follow up during the year 2013,
having as a major focus new drugs for type 2 diabetes, including GLP-1 agonists, DPP-4 inhibitors, SGLT2 inhibitors and insulin analogues.
Self-monitoring of blood glucose (SMBG). The
largest clinical trial ever performed on SMBG in
type 2 diabetes (PRISMA Study) has been con-
ducted under the coordination of the San Raffaele
group. The results indicated that the use of SMBG, structured in timing and frequency, improves
glycemic control and provides guidance in prescribing diabetes medications in noninsulin-treated patients with type 2 diabetes. This study provides relevant information into the controversial issue of clinical benefits of SMBG in this patient
population.
New treatments of diabetic complications. Following a preliminary pilot trial performed in the recent
past, we conducted a multicenter European clinical trial that validated the Frequency Modulated
Electro-Magnetic neural Stimulation (FREMS) as a
novel and original non pharmacological treatment
for symptomatic diabetic neuropathy. During the
year 2013, this innovative technology has also
been successfully applied in Scleroderma Diabeticorum, a rare and otherwise untreatable complication of diabetes.
Emanuele Bosi
Cardio-metabolism and clinical trials
New and innnovative treatments of type 2 diabetes and cardiovascular
disease
In the light to evaluate innovative treatments to revert IR and endothelial dysfunction (ED), as part of
a nutritional planning, we demonstrated that
among persons with Impaired Glucose Tolerance
(IGT) and Metabolic Syndrome (MS), the supplementation of L-arginine for 18 months significantly
increased regression to Normal Glucose Tolerance and the results were maintained during an
extended follow-up of 30 months. This interventional study demonstrated that dietary L-arginine
supplementation in conjunction with lifestyle intervention could significantly increase the conversion
of impaired glucose tolerance and metabolic syndrome to normal glucose tolerance. This study
provides a potential population-directed approach
to prevention of type 2 diabetes. In the line of a
nutritional approach to prevent type 2 diabetes, a
functional food was invented by the group, i.e. a
biscuit with a low content in sugars and proteins
and added with L-arginine that enhances endothelial function and improves glucose metabolism, insulin sensitivity and secretion in subjects
with IGT and MS. An international patent was
posted
(PCT/EP2011/068471,
number
WO2012052555) in collaboration with Cardio-Diabetes and Core Lab Unit. We are also evaluating
the role of environmental factors, i.e. smoking, in
the development of insulin resistance. The group
is also involved in the largest and major worldwide sponsored Clinical Trials for the prevention
and cure of DM2 and CAD and we have implemented our performance in these Trials and in
October 2012 our Centre was defined one of the
“Premier Site” in the world in collaboration with
Sanofi-Aventis. The Unit collaborate with the Cardio-Thoraco-Vascular and the Neurology Departments.
Piermarco Piatti
91
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Clinical Research Units
Fetal-maternal medicine
Study of new predictors of pregnancy outcomes in women with high risk
pregnancies
1. Identification of novel markers of local and systemic inflammation able to anticipate pregnancy
outcome in patients with recurrent pregnancy
losses
In collaboration with the Innate Immunity and Tissue Remodelling and the Inflammation and vascular remodelling Units (Division of Regenerative
Medicine, Stem Cells and Gene Therapy) we are
verifying the ability of novel markers of vascular
activation, systemic inflammation and coagulation
to predict maternal and foetal outcome in women
with the Anti-Phospholipid Syndrome and/or with
unexplained recurrent miscarriages, second
trimester abortions or intrauterine foetal deaths. In
the same cohort of patients we are also verifying
the presence of novel auto-antibodies specificities (i.e. the acute phase protein PTX3, protein S,
protein C) and of polymorphisms in genes that
control the development of immune tolerance versus inflammation (e.i. HLAG). In addition we are
testing how the treatment with low molecular
weight heparins interfere with the markers
analysed.
transcripts of fetal and placental genes potentially
involved in the pathogenesis of preeclampsia and
intrauterine growth restriction. The identification of
early markers of these complications of pregnancy is important for prevention and early diagnosis.
For this study we are collecting blood samples at
different gestational ages and clinical data from
patients at increased risk to develop preeclampsia and intrauterine growth restriction.
3. Screening for gestational diabetes in Lombardy: a population-based study
2. Study of feto-placentar nucleic acids in maternal plasma in preeclampsia and intrauterine
growth restriction
In Italy screening for gestational diabetes is recommended for women at increased risk, i.e.,
women with previous gestational diabetes or diabetes in first-degree relatives, obese or older
than 35 years of age or from geographical areas
at increased risk of type 2 diabetes. Current
practice and compliance to screening guidelines
has never been documented. In collaboration
with the Department of Biostatistics of the University of Milano Bicocca and the Diabetes Research Institute we are analyzing regional Health
Care System archives to document the screening practice for gestational diabetes in over
360.000 pregnancies in the Lombardy Region in
the period 2007-2010.
We are collaborating with the Genomic Unit for Diagnosis of Human Pathologies to test a panel of
Maria Teresa Castiglioni
Clinical pediatric endocrinology
The main fields of research of the pediatric endocrinology unit are thyroid diseases, short
stature, Congenital Adrenal Hyperplasia (CAH),
Hypogonadotrophic Hypogonadism, Disorders of
sex differentiation (DSD). As regards Congenital
Hypothyroidism (CH) we continued a collaborative
research project with the University of Milan to expand our knowledge on the genetic, epigenetic
and environmental factors contributing to CH. We
also focused on the thyroid function in twins and
preterm babies positive at screening programme
for CH. Concerning this topic, our attention has
been focused on the aetiological and peculiar
clinical aspects of CH in twins, and we have studied the outcome of thyroid function in the group.
As co-investigator of AIFA Research we continued
the study that evaluates the influence of initial
Levothyroxine dose at diagnosis on neurodevel-
opmental, growth, cardiovascular and skeletal
outcomes in children with CH. We participated in
some multicentric studies on hyperthyroidism,
evaluating the possible prognostic factors for recovery after medical treatment. We conducted a
study on relevant clinical and auxologic aspects in
Noonan patients: we evaluated the response to
Growth Hormone in short syndromic children, in
terms of growth velocity and short term height
gain (3 years of therapy) and its correlation to
genotype (PTPN11 + and PTPN11 - patients).
Congenital Adrenal Hyperplasia (CAH) is a field of
application of less-invasive and more accurate
methods. We are continuing to determine serum,
salivary and urinary steroid profile through LC-MS
for diagnosis and follow-up of various forms of
CAH. Hypogonadotrophic Hypogonadism is a
family of diseases that could have a neonatal, pu-
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
bertal or adult onset. We continued to study these
patients from a clinical and a genetic perspective.
In some patients, mutations in candidate genes
have been found. Disorders of sex differentiation
(DSD) comprehend congenital conditions in
which chromosomal, gonadic and anatomic development is atypical. We aim to standardize
pharmacologic tests execution and results interpretation in order to obtain a better diagnostic
definition, together with genetic analysis. A diagnosis is obtained in 66% of patients with DSD and
46XY karyotype.
Giovanna Weber
Diabetes and metabolic diseases in children and adolescents
The aim of the diabetes unit is clinical research in
children and adolescents with type 1 diabetes in
a large outpatients clinic attended by 750 subjects with diabetes.
We have 3 main lines of study: 1) prevention of diabetes; 2) technology in diabetes; 3) Genetic and
metabolic study in infants with neonatal insulin resistant diabetes.
More than 250 children treated with pump for continuous subcutaneous insulin infusion (CSII) are in
follow-up for many years and we have compared
CSII and multiple daily injections (MDI) in children <
6 yrs and investigated technical and clinical failures
with a review of a large number of patients.
In cooperation with Prof Barbetti ( Bambino Gesù
Hospital - Rome ) we are studying correlation
phenotype-genotype in insulin resistant diabetes
due to insulin receptor gene mutations and incidence of neonatal/infancy onset diabetes in Italy.
We are an active part of SIEDP’s group in pediatric diabetology and we participate in different
multicenter studies.
We collaborate in Trialnet (directed by Prof. Bosi),
primary and secondary prevention study, and with
Dr. Battaglia (of Diabetes Research Institute ) in
evaluating innate cells role in children affected by
type 1 diabetes.
The obesity unit is performing clinical research in
children and adolescents with Prader-Willi Syndrome (PWS), the most common genetic cause
of obesity, characterized by elevated morbidity
and mortality in all ages. In collaboration with others Italian Research centre we investigated different aspects:
• the effects of long-term GH therapy on sleepdisordered breathing and adenotonsillar hypertrophy in children with PWS
• the prevalence of central adrenal insufficiency in
Prader-Willi syndrome using the metyrapone
test
• the occurrence of metabolic syndrome and its
components in a large group of PWS, according to obesity status.
Another field of interest is congenital hyperinsulinism of infancy (CHI) a rare disease that needs
prompt treatment to avoid brain damage. We
studied the clinical and molecular features of 33
patients with CHI and their parents. This is the first
report on hyperinsulinism of infancy in Italy.
Moreover, in order to search for novel loci contributing to the pathogenesis of CHI, we combined a family-based association study, using the
transmission disequilibrium test on 17 CHI patients lacking mutations in ABCC8/KCNJ11, with
a whole-exome sequencing analysis performed
on 10 probands. This strategy allowed the identification of the potential causative mutations in
genes implicated in the regulation of insulin secretion.
Franco Meschi
Neonatology
The main clinical activity of our Unit is the assistance to healthy and premature newborn (about
2.100/ year) with support of the local intensive
care unit.
Offspring of mothers with gestational diabetes
and neonatal endocrine disease are clinical excellence area of our unit. We pay specially attention
to quality of care as preterm infant developmental
care in ELBW infants,through strict control of all
the environmental challenges.
Research Fields
The main research interest in Neonatology deals
with three clinical fields.
Maturative study of the Central Nervous System.
Study of CNS is a very fascinating field of research and using innovative approaches, such as
Diffusion Tensor Imaging and Functional MRI, it is
possible to quantify the anatomic and functional
evolution of the brain of the preterm babies. Our
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DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Clinical Research Units
group co-operates with the department of Pediatric Neuroradiology for the application of the latest imaging techniques and to valuate the clinical
feasibility.
Metabolic and clinical outcome of infants born
pre-term or from mothers with diabetes. Infants
born from pregnancies complicated by pre-gestational or gestational diabetes, whose clinical conditions are often similar to those of uncomplicated
pregnancies, need more characterization in order
to better define their long-term clinical and metabolic outcome. Body composition and bone mineralization are innovative fields of research, that
we are exploring in such babies along with growth
and neuro-psychologic development. The aim is
to evaluate the impact of pre-gestational condi-
tions on extra-uterine growth. Results are than
compared with normal babies an with infants born
pre-term or small for gestational age.
New molecular methods for detecting severe infections in newborn infants. Early diagnosis of
sepsis is an important challenge in newborns: validation of molecular assay detecting bacteria DNA
in blood could be an useful tool for early diagnosis
and therapy. Preliminary datas, obtained by collaborating with Microbiology Department suggest that
molecular microbiological techniques are both instruments for possible microbiological diagnosis and
potential markers potentially used in the clinical management of non-infection conditions as gut perforation in necrotising enterocolitis
Graziano Barera
Structural heart disease Unit
Heart failure
Ischemic heart disease
Surgical strategies to treat patients with heart failure are investigated. Original procedures to correct secondary mitral and tricuspid regurgitation
have been developed. Mid- and long-term results of the procedures on tricuspid valve have
been evaluated and a randomized study is ongoing to establish indications for the correction of
tricuspid pathology. Surgical approaches alternative to transplant have been investigated as therapies for the late stage heart-failure including
ventricular assist devices. Surgical repair of the
mitral valve has been deeply investigated in the
context of dilatative cardiomyopathy, even associated to atrial fibrillation ablation and resynchronization therapy.
Active contribution has been given to the SYNTAX
study, the FREEDOM study and the EXCEL study,
all comparing PCI and CABG in multivessel and
main stem disease.
Heart valve disease
Innovative techniques to repair mitral and aortic
valve have been systematically evaluated. New
imaging modalities have been applied and correlated to the operative findings. Experimental adjustable devices for mitral valve repair have been
designed and evaluated. Very long term results of
the edge-to-edge repair (an original technique of
MR correction introduced by our group) have
been assessed and reported at international
meetings.
Atrial fibrillation
New surgical methods to increase the effectiveness of the atrial fibrillation ablation procedures,
during open heart surgery, have been developed.
A program for the treatment of lone atrial fibrillation
via a minimally invasive approach has been implemented, and new technologies have been introduced and meticulously tested. The left atrial remodeling has been studied not only structurally
but also at molecular and biochemical level. Morphologic and structural changes of the cardiomyocytes in atrial fibrillation have been investigated.
Devices to exclude the left atrial appendage are
tested and evaluated.
Transcatheter valve therapy
A multidisciplinary program for transcatheter aortic, mitral and tricuspid valve therapy has been
developed using a wide spectrum of techniques
and technologies. Guidelines have been prepared and extensive investigation in this area are
ongoing.
Ottavio Alfieri
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Cardiopulmonary clinical physiology Unit
Research has focused on early diagnosis of small
airway disease using impulse oscillometry and
multiple breath nitrogen washout in subjects with
asthma and in recipients of bone marrow transplantation with bronchiolitis obliterans
The gold standard for the diagnosis of bronchial
asthma in patients with a normal spirometry is currently the methacholine challenge test (MCT) test.
IOS is a promising technique to assess airway
function able to quantify changes in peripheral airway resistance undetected by traditional spirometry.
Non smoking patients were studied by spirometry
and IOS prior to MCT. Mean baseline FEV1 was
normal. Ten subjects had a positive MCT. IOS
showed higher baseline R5-20Hz values in MCT+
subjects (p2O/l/s. Rp may be a useful marker in
predicting MCT response and provide a screening tool for detecting bronchial asthma.
Bronchiolitis Obliterans (BO) initially affects terminal and respiratory bronchioles, a region of the
lung largely unexplored by spirometry. Multiple nitrogen wash out (N2-MBW ) is shows a high sen-
sitivity to peripheral airway changes potentially
more suited to early detection of small airways
disease.
Healthy controls (n=41), bone marrow transplant
candidates (n=47), haematopoietic stem cell
transplantation (HSCT) recipients (n=65) and patients with COPD (n=8), were assessed by N2MBW and spirometry. HSCT enhanced ventilation
inhomogeneity both in conductive (Scond*VT)
and acinar (Sacin*VT) airways. Patients with BO
(n=8) were characterized by a further 3-fold increase in Sacin*VT more than twice that in COPD
patients. At 321% of predicted, Sacin*VT could
distinguish the subjects with BO from recipients,
with 87% accuracy, 88% sensibility and 90%
specificity. N2-MBW is able to detect changes
following HSCT as well as those specific to BO.
Data presented at the annual meeting of the European Respiratory Society Barcelona September
2013 and the 55th ASH Annual Meeting and Exposition (December 7-10, 2013) in New Orleans,
LA.
George Cremona
Cardiovascular interventions Unit
Coronary artery disease: PARTICIPATE is a
prospective observational study evaluating polymer Cre8 stent ”de-novo”coronary artery.
Acute Coronary Syndromes, ACS: MATRIX is a
randomized clinical trial evaluating in patients with
ACS trans-radial intervention as compared to
femoral access site and bivalirudin vs. unfractionated heparin±GP IIb/IIIa inhibitor.
High risk patients, LEADERS FREE is a prospective randomized clinical trial evaluating bare metal
stent versus Biofreedom stent in patients at high
risk for bleeding. Complex Coronary Lesions:The
EXCEL trial is a randomized trial comparing
Everolimus eluting coronary stent system vs.
coronary artery bypass graft surgery in subjects
with unprotected left main coronary artery disease
and low to intermediate SYNTAX scores.
Treatment of bifurcation coronary lesions: The
OPEN II is a prospective observational study evaluating the long-term safety and efficacy of the
STENTYS stent. The Sideguard Coronary Sidebranch Registry(SGR1) is a prospective observational registry evaluating Bare Metal Sidebranch
Stent.
Bioabsorbable vessel scaffolds (BVS):PABLOS
Prospective observational registry evaluating the
use of Absorb BVS specifically in patients with bifurcation lesions.
Adjunctive therapy trials: the duration of dual antiplatelet therapy (6 vs.12 months) is currently being investigated in the SECURITY study. STATIPLAT is a randomized trial evaluating the effect on
platelet reactivity of the high dosage of Atorvastatin vs Rosuvastatin administrated before PCI.
Structural Heart Disease/Transcatheter valve therapy: the DIRECT FLOW IP 010 is a prospective, multicenter, non-randomized clinical trial to determine
the safety and performance of the Direct Flow Medical Percutaneous Aortic Valve 18F System for the
treatment of severe aortic stenosis. The primary endpoint is freedom from all-cause mortality from procedure to 30 days. WIN TAVI is a prospective observational multinational study evaluating TAVI procedures specifically in women. Others: OneShot is
a prospective observational study evaluating One
Shot Ablation System for renal denervation in patient with refractory hypertension. EKOSONIC is a
prospective observational registry evaluating safety and efficacy of loco regional trombolysis using
Ekosonic catheter in patients with sub and massive
pulmonary embolism.
Antonio Colombo
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DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Clinical Research Units
Center for arrhythmia research
The main research topic of our group is the improvement in the management of patients with
complex arrhythmias. The following projects
about VT management are currently in progress at
our Institution:
storm (Group B). The main objective of this second B Phase is to compare the 2-year rate of
worsening Heart Failure hospitalizations, deaths,
cardiac death, VT recurrences and Electrical Storm
recurrences between the two groups.
1) Role of substrate modification aimed to the
electroanatomic definition of areas with abnormal
potential and their complete elimination
3) Radio-frequency ablation as primary management of well-tolerated sustained monomorphic
ventricular tachycardia in patients with structural
heart disease and left ventricular ejection fraction
over 30%
The inconsistent inducibility of the index VT at
baseline programmed stimulation study may limit
the value of programmed electrical stimulation.
We investigated the ventricular tachycardia substrate in patients affected by myocarditis, Ischemic heart disease, Idiopathic Dilated Cardiomyopathy, Arrhythmogenic Right Ventricular
Cardiomyopathy.
2) Identification of the appropriate timing for VT
ablation in patients with structural heart disease.
The PARTITA trial
We planned a multicentric, controlled, singleblinded trial to evaluate if the timing of VT ablation
significantly affects the patient’s prognosis. The
PARTITA study will consist of a prospective data
collection (Phase A) and a prospective randomized
study period (Phase B). After the first appropriate
ICD shock for VT, patient will enter the Phase B and
they will be randomized to immediate VT ablation
(Group A) or to ablation after the first arrhythmic
Patients with well-tolerated sustained monomorphic ventricular tachycardia (SMVT) and left ventricular ejection fraction (LVEF) over 30% may benefit from a primary strategy of VT ablation without
immediate need for a ‘back-up’ implantable cardioverter-defibrillator (ICD). This approach was
evaluated in a multicenter study.
4) Bipolar radiofrequency ablation
Unipolar radiofrequency ablation is known to produce superficial lesions; this approach may be ineffective in the treatment of patients with tachicardias originating from deep myocardial tissue.
Bipolar radiofrequency ablation is supposed to
produce more deep lesion and increase the percentage of transmural ablations. We will assess if
bipolar ablation allows better clinical results compared to unipolar technique.
Paolo Della Bella
Echocardiography Unit
The Echo Unit focuses on clinical imaging research:
• accuracy of 3-Dimensional Echo for functional
mitral valve anatomy in patients with mitral regurgitation, using standard anatomical surgical
findings;
• outcome research on 3D echo-guided surgical
mitral valve repair;
• Left ventricle fluid dynamics analysis;
• clinical outcome research on surgical myectomy or percutaneous septal alcoholization for the
treatment of Obstructive Hypertrophic Car-
diomyopathy;
• 3-Dimensional Echo in the setting of percutaneous valve therapy, including MitraClip Therapy
and Transcatheter Aortic Valve Implantation;
• Clinical Outcome research on MitraClip Therapy
for functional mitral regurgitation in patients with
congestive heart failure;
• Tricuspid Valve Assessment using 3D Echo to
predict the mechanism and late valve regurgitation after correction of left-sided valve disease;
• Imaging support for technical innovation in the
surgical department.
Giovanni La Canna
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Figure 16. Left Ventricle Fluid dynamics analysis.
Ischaemic heart disease, heart failure and
echocardiography Unit
Study of cellular and metabolic adaptation and evaulation of potential
prognostic and therapeutic implications in heart failure
1. Investigations on the potential presence and
the functional role of specific mitochondrial proteins in patients with chronic heart failure. More
specifically, we intend to continue the performance of endomyocardial biopsies in patients with
various degrees of cardiac dysfunction. The samples will be analyzed with a specific antibody
against intramitochondrial ferritin. In presence of
reduced contractile function, the heart could evidence increased expression of mitochondrial ferritin either as a protective effect or as a marker of
intracellular iron storage. In both conditions, monitoring intramitochondrial ferritin and its correlation
with cardiac function could be very useful in order
to evaluate the role of cellular expression of this
protein in both ischemic and non ischemic dilatative cardiomyopathy.
2. Additional studies we intend to continue in the
years 2014-2015 are aimed at evaluating the effects of metabolic drugs on cardiac function and
metabolism in patients with chronic heart failure.
In facts, the observed gross metabolic derangements in patients with heart failure, are often increased by a state of insulin resistance and increased levels of xanthine-oxidase. These conditions worsen the metabolic and functional adaptation of the failing heart. Furthermore, we intend to
evaluate the effects of ivabradine versus beta
blockers in patients with heart failure and functional mitral regurgitation. The aim is to evaluate the
efficacy in terms of reduction of the regurgitant
fraction associated to improved left and right ventricular function, and reduced pulmonary artery
pressure.
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DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Clinical Research Units
Aims:
• Role of pulmonary ultrasound and non invasive
determination of central venous pressure in the
optimization of medical therapy in the clinical follow-up of patients with chronic heart failure. The
primary end-point is the reduction of hospital
admissions for worsening heart failure, while the
secondary end-point is the reduction of mortality. More specifically, subgroups analysis will
evaluate the adjunctive value in patients without
clinical signs of congestion and negative heart
failure biomarkers.
• We will continue the research in the field of
characterization and outcome of functional mitral regurgitation in patients with left ventricular
dysfunction.
• Diagnostic characterization and outcome of
functional tricuspid regurgitation in patients with
left ventricular dysfunction.
• Finally, echocardiographic evaluation of atrial
function and its significance in terms of clinical
symptoms in patients with organic mitral valve
regurgitation will be evaluated by strain analysis.
Alberto Margonato
Organ protection in critically ill patients, Advanced
cardiac failure and mechanical supports Unit
Organ failure in critically ill patients is associated to
high morbidity and mortality. Our research focuses on the implementation of advanced mechanical supports to the cardiovascular and respiratory
system and on the reduction of perioperative mortality.
• ECMO (Extracorporeal Membrane Oxygenation), VAD (Ventricular Assist Device), artificial
heart and other advanced mechanical and
pharmacological supports of the circulation for
the treatment of acute heart failure or for refractory hypoxia. We coordinate national networks
performing mRCTs and we collaborate with international centers.
• Non-invasive ventilation in critically ill patients
even outside the intensive care unit including
the development of new devices.
• Protective intra-operative ventilation: participation in multicenter studies to clarify the role of
mechanical ventilation settings during general
anesthesia on post-operative pulmonary complications.
• Alternative procoagulant and anticoagulants in
the perioperative period with participation to
mRCTs.
• The role of volatile anesthetics in perioperative
cardioprotection coordinating mRCTs.
• Reduction of perioperative mortality and perioperative acute myocardial infarction: role of betablockers, inotropic agents, antiplatelet agents,
and clonidine including the participation in inter-
national studies as Italian national coordinator
center.
• Prevention and treatment of acute renal failure
and perioperative organ damage in critically ill
patients, coordinating large mRCTs at the Italian
level.
• The role of metabolomics in the identification of
different metabolic phenotypes associated with
the development of specific outcomes.
• Role of ultrasound in the study of diaphragmatic
function.
• Cardiac biomarkers (proBNP, cardiac troponin)
and Renal biomarkers (ouabaine).
• Sepsis in intensive care.
• Intra and extra-hospital emergencies.
• Anesthesiological management of the patient
with a very high periprocedural risk.
• Antibiotic therapy in intensive care.
• Control of perioperative pain.
• Coordination of an international network through
innovative web-based consensus conferences;
• Indexing on Pubmed of the international journal
“Heart, Lung and Vessels”, freely available at
www.heartlungandvessels.org
With over 50 manuscripts published on the above
described topics in indexed journals yearly we are
the most prolific Italian group publishing in anesthesia and intensive care journals.
Alberto Zangrillo
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Strategic research on heart failure Unit
CORONARY MICROVASCULAR DYSFUNCTION
Hypertrophic Cardiomyopathy (HCM)
Pilot multicenter, double blind, randomized study
to assess the effect of Ranolazine on functional
capacity and diastolic function in patients (n=10)
with HCM which has been completed.
Systemic Sclerosis (SS)
To identify prevalence of In patients with SS coronary microvascular dysfunction (CMD) is more
prevalent in patients than in controls (10/19 vs
0/20; p
Hypertensive Heart Disease
1. Clinical. Multicenter randomized study to evaluate the effect of the direct renin inhibitor aliskiren
on CMD in hypertension as compared with ACEinhibitor enalapril. The primary endpoint of the
study is the change in myocardial blood flow and
flow reserve measured with PET (positron emission tomography).
2. Spontaneously hypertensive rat (SHR). To
study effect of several drugs used in hypertension
such as ACE inhibitor, beta blockers and calcium
antagonist on microcirculation in SHR in addition
to molecular characterization of several genes
known to be involved in remodelling processes.
Prospective validation of PET/computerized (CT)
with 11C-PK11195 and contrast-enhanced ultrasound imaging of intraplaque neovascularization
in asymptomatic patients with carotid atherosclerosis as a predictor of plaque vulnerability assessed by burden of cerebral ischemic lesions
detected by repeated magnetic resonance (RM)
studies.
Number of patients enrolled: 52/60 Asymptomatic patients with carotid plaque; 9/20 symptomatic patients with carotid plaque.
MYOCARDIAL ISCHEMIA AND LEFT VENTRICULAR DYSFUNCTION
1. Repetitive stunning and left ventricular dysfunction: effect of Ivabradine
To evaluate the effect of ivabradine on post-ischemic stunning during exercise echocardiography in patients with known CAD. Number of patients enrolled: 13/15.
2. Ischemia-Reperfusion Injury: No Reflow Phenomenon
Prospective study to compare no reflow diagnostic accuracy and prognostic stratification value of
cardiac magnetic resonance versus coronary angiography in patients with ST-segment elevation
acute myocardial infarction. Number of patients
enrolled: 62.
NON INVASIVE STRATEGY FOR DETECTION OF
VULNERABLE ATHEROSCLEROTIC PLAQUES
Paolo G. Camici
Study and treatment of aortic disease Unit
In 2013 the Vascular Surgery Unit of the IRCCS
Ospedale San Raffaele has been involved in several clinical research studies regarding vascular
pathology, in particular on the treatment of aortic
disease, including:
• RESTORE TRAUMA Sub-Study, focused on the
endovascular treatment of traumatic injuries of
the thoracic aorta (results published in Zipfel B,
Chiesa R, Kahlberg A, et al. Ann Thorac Surg.
2014 Mar;97(3):774-80).
• INNOVATION Trial: it is a multicenter, open label,
prospective, non-randomized trial of INCRAFTT
stent-graft in subjects with abdominal aortic
aneurysms (results published in Coppi G, Njila
M, … Chiesa R, et al. J Cardiovasc Surg (Torino). 2014 Feb;55(1):51-9.)
• The Ovation Abdominal Stent Graft System
Post-Market Study, an international study to
evaluate the safety and performance of the
TriVascular AAA Stent Graft System.
• STABLE Trial: endovascular treatment of complicated type B aortic dissection with a new composite device design (results published in Lombardi JV, Cambria RP, …Chiesa R, et al. J Vasc
Surg. 2014 Feb 19, in press.)
• SAFROS: Patient Safety in Robotic Surgery.
Aim of the study is to define patient safety metrics, to develop methods that abide by safety
requirements and to demonstrate that a properly controlled robotic surgery can improve the
level of patient’s safety.
• Evaluation of the effect of renal perfusion with
histidine-tryptophan-ketoglutarate hypothermic
solution during thoracoabdominal aortic repair
(results published in Tshomba Y, Kahlberg A,
Melissano G,… Chiesa R. J Vasc Surg. 2014
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DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Clinical Research Units
Mar;59(3):623-33)
• Use of “GORE Hybrid Vascular Graft” for renal
artery revascularization during thoracoabdominal aortic repair in order to reduce the renal ischemia time during surgery and the postoperative renal complications (results currently in
press).
• European Registry of Endovascular Aortic Repair Complications (EuREC 4), on aortoesophageal fistulae developing after thoracic
aortic endovascular repair (results published in
Czerny M, Eggebrecht H, … Chiesa R, et al.
Eur J Cardiothorac Surg. 2014 Mar;45(3):4527.
During 2013 the Vascular Surgery Unit has also
published 14 papers on peer reviewed journals,
regarding the treatment of aortic disease and other aspects of vascular pathology.
Roberto Chiesa
Vision first Unit
Surgical retina
Orbital Surgery
CR: Characterization of myopic macular hole with
posterior pole detachment after surgical closure
with inverted flap technique. Vitreoretinal interface
prognostic characterization in vitreomacular traction.
BR: Dynamic Vessel Analyzer (DVA) of retinal vessels after macular vitreoretinal surgery.
CR: New therapeutic strategies of ocular MALT
lymphomas.
Medical retina
CR: DVA retinal vessel changes after Ozurdex/anti-VEGF treatment for Retinal Vein Occlusion and
diabetic macular edema. DVA retinal vessel and
EDI-OCT choroid characterization in reticular
pseudodrusen. Influence of refractive status, caffein and wine intake on DVA. New therapeutic options and algorithms with intravitreal compounds
for macular disorders. Applications of Drug Delivery Systems. Diagnosis and imaging of macular
dystrophies
BR: Retinal and choroidal structure in-vivo longlasting diabetes mouse model. Citicoline topical
treatment. Chromogranin A-derived Vasostatin-1
on laser-induced choroidal neovascularization in
the mouse.
Ocular immunology and uveitis
CR: New biologic agents for intraocular inflammation.
Ocular Oncology
CR: Gamma Knife Radiosurgery (GKR) treatment
in uveal melanoma and intralesional injection of
Rituximab in conjunctival lymphoma.
Imaging
CR: GCC and choroidal thickness in patients with
diabetes and connective tissue disease with Reynaud phenomenon. DVA of retinal vessels in patients with Reynaud phenomenon. GCC thickness in AMD after anti-VEGF intravitreal injection.
Choroidal thickness in treated posterior uveitis.
Anterior segment surgery
CR: Quality of life in low vision subjects implanted
with a +8D multifocal lens. European population
large scale database of human ocular biometry
values. Intracameral anaesthetic and mydriatic solution for cataract surgery.
Glaucoma
CR: New medical and surgical therapeutic options in glaucoma.
Neuro-ophthalmology
CR: Surgical decompression and GKR on pituitary tumors compressing visual pathways. Brain
damage and visual network plasticity in neurodegenerative diseases. Citicoline treatment and
neurodegenerative disorders. Orbital RM alterations in patients with Graves disease. Ophthalmic artery, central retinal artery and vein, short
posterior ciliary arteries Ecocolordoppler in LHON
and DOA patients.
Francesco Bandello
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Selected publications
Bosi, E; Scavini, M; Ceriello, A; Cucinotta, D; Tiengo, A; Marino, R; Bonizzoni, E; Giorgino, F; on
behalf of the PRISMA STUDY GROUP. Intensive structured self-monitoring of blood glucose and
glycemic control in noninsulin-treated type 2 diabetes: the PRISMA randomized trial. Diabetes Care:
2013; 36(10): 2887-2894 - Article
IF 2012: 7,735
Bosi, E; Bax, G; Scionti, L; Spallone, V; Tesfaye, S; Valensi, P; Ziegler, D; on behalf of the FREMS
European Trial Study Group. Frequency-modulated electromagnetic neural stimulation (FREMS) as a
treatment for symptomatic diabetic neuropathy: results from a double-blind, randomised, multicentre, long-term, placebo-controlled clinical trial. Diabetologia: 2013; 56(3): 467-475 - Article
IF 2012: 6,487
Taramasso, M; Latib, A; Denti, P; Candreva, A; Buzzatti, N; Giannini, F; La Canna, G; Colombo, A; Alfieri, O; Maisano, F. Acute kidney injury following MitraClip implantation in high risk patients: Incidence, predictive factors and prognostic value. Int. J. Cardiol.: 2013; 169(2): e24-e25 Letter
IF 2012: 5,509
Franzoni, I and Latib, A; Maisano, F; Costopoulos, C; Testa, L; Figini, F; Giannini, F;
Basavarajaiah, S; Mussardo, M; Slavich, M; Taramasso, M; Cioni, M; Longoni, M; Ferrarello,
S; Radinovic, A; Sala, S; Ajello, S; Sticchi, A; Giglio, M; Agricola, E; Chieffo, A; Montorfano,
M; Alfieri, O; Colombo, A. Comparison of incidence and predictors of left bundle branch block after transcatheter aortic valve implantation using the corevalve versus the edwards valve. Am. J. Cardiol.: 2013; 112(4): 554-559 - Article
IF 2012: 3,209
Piscopiello, M; Sessa, M; Anzalone, N; Castellano, R; Maisano, F; Ferrero, E; Chiesa, R; Alfieri, O; Comi, G; Ferrero, ME; Foglieni, C. P2X7 receptor is expressed in human vessels and
might play a role in atherosclerosis. Int. J. Cardiol.: 2013; 168(3): 2863-2866 - Letter
IF 2012: 5,509
Della Bella, P; Baratto, F; Tsiachris, D; Trevisi, N; Vergara, P; Bisceglia, C; Petracca, F; Carbucicchio, C; Benussi, S; Maisano, F; Alfieri, O; Pappalardo, F; Zangrillo, A; Maccabelli, G. Management of ventricular tachycardia in the setting of a dedicated unit for the treatment of complex
ventricular arrhythmias: Long-term outcome after ablation. Circulation: 2013; 127(13): 1359-1368 Article
IF 2012: 15,202
Godino, C; Lauretta, L; Pavon, AG; Mangieri, A; Viani, G; Chieffo, A; Galaverna, S; Latib, A;
Montorfano, M; Cappelletti, A; Maisano, F; Alfieri, O; Margonato, A; Colombo, A. Heyde’s syndrome incidence and outcome in patients undergoing transcatheter aortic valve implantation. J. Am.
Coll. Cardiol.: 2013; 61(6): 687-689 - Letter
IF 2012: 14,086
Grimaldi, A; Figini, F; Maisano, F; Montorfano, M; Chieffo, A; Latib, A; Pappalardo, F; Spagnolo, P; Cioni, M; Vermi, AC; Ferrarello, S; Piraino, D; Cammalleri, V; Ammirati, E; Sacco,
FM; Arendar, I; Collu, E; La Canna, G; Alfieri, O; Colombo, A. Clinical outcome and quality of life
in octogenarians following transcatheter aortic valve implantation (TAVI) for symptomatic aortic stenosis. Int. J. Cardiol.: 2013; 168(1): 281-286 - Article
IF 2012: 5,509
Chieffo, A and Buchanan, GL; Van Mieghem, NM; Tchetche, D; Dumonteil, N; Latib, A; Van Der
Boon, RMA; Vahdat, O; Marcheix, B; Farah, B; Serruys, PW; Fajadet, J; Carrie, D; De Jaegere, PPT;
Colombo, A. Transcatheter aortic valve implantation with the Edwards SAPIEN versus the medtronic corevalve revalving system devices: A multicenter collaborative study: The PRAGMATIC plus initiative (Pooled-RotterdAm-Milano-Toulouse in Collaboration). J. Am. Coll. Cardiol.: 2013; 61(8): 830836 - Article
IF 2012: 14,086
Barile, L; Landoni, G; Pieri, M; Ruggeri, L; Maj, G; Nigro Neto, C; Pasin, L; Cabrini, L; Zangrillo,
A. Cardiac index assessment by the pressure recording analytic method in critically ill unstable patients after cardiac surgery. J. Cardiothorac. Vasc. Anesth.: 2013; 27(6): 1108-1113 - Article
IF 2012: 1,448
101
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Selected publications
Godino, C; Bassanelli, G; Economou, FI; Takagi, K; Ancona, M; Galaverna, S; Mangieri, A;
Magni, V; Latib, A; Chieffo, A; Carlino, M; Montorfano, M; Cappelletti, A; Margonato, A;
Colombo, A. Predictors of cardiac death in patients with coronary chronic total occlusion not revascularized by PCI. Int. J. Cardiol.: 2013; 168(2): 1402-1409 - Article
IF 2012: 5,509
Agricola, E and Slavich, M; Tufaro, V; Fisicaro, A; Oppizzi, M; Melissano, G; Bertoglio, L;
Marone, E; Civilini, E; Margonato, A; Chiesa, R. Prevalence of thoracic ascending aortic
aneurysm in adult patients with known abdominal aortic aneurysm: An echocardiographic study. Int.
J. Cardiol.: 2013; 168(3): 3147-3148 - Letter
IF 2012: 5,509
Fragasso, G; Rosano, G; Baek, SH; Sisakian, H; Di Napoli, P; Alberti, L; Calori, G; Kang, SM; Sahakyan, L; Sanosyan, A; Vitale, C; Marazzi, G; Margonato, A; Belardinelli, R. Effect of partial fatty
acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: Results from an
international multicentre retrospective cohort study. Int. J. Cardiol.: 2013; 163(3): 320-325 - Article
IF 2012: 5,509
Marrocco-Trischitta, MM; Cremona, G; Lucini, D; Natali-Sora, MG; Cursi, M; Cianflone, D;
Pagani, M; Chiesa, R. Peripheral baroreflex and chemoreflex function after eversion carotid endarterectomy. J. Vasc. Surg.: 2013; 58(1): 136-144.e1 - Article
IF 2012: 2,879
Bertoglio, L; Melissano, G; Civilini, E; Chiesa, R. Stent misalignment of the Zenith Dissection Endovascular System. J. Vasc. Surg.: 2013; 57(2): 515-517 - Article
IF 2012: 2,879
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Coagulation and platelet biology Unit
Complications of diabetes
103
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Pediatric endocrinology research
Diabetes and metabolic diseases in children and adolescents
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Neonatology
Echocardiography Unit
105
DIVISION
OF
REGENERATIVE
MEDICINE,
STEM CELLS AND GENE THERAPY
Director:
Luigi Naldini*
Associate Director:
Fabio Ciceri
Research Units
Angiogenesis and tumor targeting Unit ––––––––––––––––––––––––––––––––––––––––––––––––– 113
HEAD OF UNIT: Luigi Naldini*
POST-DOCTORAL FELLOW: Erika Zonari
PHD STUDENT: Giulia Escobar**
TECHNICIAN: Anna Ranghetti
Functional genetics of muscle regeneration ––––––––––––––––––––––––––––––––––– 113
GROUP LEADER: Silvia Brunelli
POST-DOCTORAL FELLOWS: Valentina Conti, Thierry Touvier, Paola Zordan
PHD STUDENT: Mario Tirone
Neural stem cell biology –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 114
GROUP LEADER: Rossella Galli
PHD STUDENTS: Katayoun Hemmesi**, Ashwin Narayanan
Autoimmunity & vascular inflammation Unit ––––––––––––––––––––––––––––––––––––––––––– 114
HEAD OF UNIT: Angelo A. Manfredi*
POST-DOCTORAL FELLOWS: Chiara Gualteroni, Norma Maugeri
PHD STUDENT: Lucia Cottone**
TECHNICIAN: Annalisa Capobianco
Innate immunity and tissue remodelling –––––––––––––––––––––––––––––––––––––––– 115
GROUP LEADER: Patrizia Rovere-Querini*
POST-DOCTORAL FELLOWS: Gianfranca Corna, Elena Rigamonti
PHD STUDENT: Imma Caserta**
TECHNICIANS: Antonella Monno, Clara Sciorati
107
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Research Units/Clinical Research Units
Experimental hematology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 116
HEAD OF UNIT: Chiara Bonini
POST-DOCTORAL FELLOWS: Nicoletta Cieri, Sara Mastaglio, Maddalena Noviello
PHD STUDENT: Giacomo Oliveira**
TECHNICIANS: Barbara Camisa, Zulma Magnani
Gene expression and muscular dystrophy Unit (Dulbecco Telethon Institute) –– 117
GROUP LEADER: Davide Gabellini, ERC Starting Grant
POST-DOCTORAL FELLOWS: Mathivanan Jothi, Marie Victoire Neguembor
PHD STUDENTS: Valentina Casà**, Claudia Huichalaf**, Valeria Runfola**
FELLOW: Giulia Ferri
TECHNICIANS: Roberta Caccia, Stefano Micheloni
Leukemia immunotherapy Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 118
GROUP LEADER: Attilio Bondanza*
POST-DOCTORAL FELLOW: Monica Casucci
PHD STUDENTS: Benedetta Nicolis di Robilant**, Margherita Norelli
FELLOWS: Laura Falcone, Fabiana Gullotta
Molecular and functional immunogenetics Unit –––––––––––––––––––––––––––––––––––––– 118
HEAD OF UNIT: Fabio Ciceri (ad interim)
POST-DOCTORAL FELLOWS: Gabriele Bucci, Cristina Toffalori, Luca Vago
PHD STUDENT: Giacomo Oliveira
FELLOW: Lara Crucitti
TECHNICIAN: Laura Zito
Clinical Research Units
Hematology and hematopoietic stem cell transplantation Unit ––––––––––––––––––– 119
HEAD OF UNIT: Fabio Ciceri
PHYSICIANS: Andrea Assanelli, Fabio Giglio, Maria Teresa Lupo Stanghellini, Sarah Marktel,
Mara Morelli, Jacopo Peccatori
RESIDENTS: Raffaella Greco**, Luca Vago**
Immunohematology and transfusion medicine Unit –––––––––––––––––––––––––––––––––– 119
HEAD OF UNIT: Fabio Ciceri
RESEARCHERS: Laura Bellio, Simona Malato, Oriana Perini, Michela Tassara
FELLOW: Annika Calloni
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
HSR-TIGET
The San Raffaele Telethon Institute
for Gene Therapy
Director:
Luigi Naldini*
Research Units
Gene transfer technologies and new gene therapy strategies Unit –––––––––––––– 121
HEAD OF UNIT: Luigi Naldini*, ERC Advanced Grant
PROJECT LEADERS: Bernhard Gentner, Anna Kajaste-Rudnitski, Angelo Lombardo
POST-DOCTORAL FELLOWS: Alessio Cantore, Amy Patel**
PHD STUDENTS: Angelo Amabile, Francesco Boccalatte**, Claudia Firrito, Pietro Genovese**,
Alice Giustacchini**(until September 2013)
FELLOW: Carolina Petrillo
LAB MANAGERS: Mauro Biffi, Tiziano Di Tomaso
TECHNICIANS: Sara Bartolaccini, Tiziana Plati, Lucia Sergi Sergi
Gene/Neural stem cell therapy for lysosomal storage diseases –––––––––––– 121
GROUP LEADER: Angela Gritti
POST-DOCTORAL FELLOWS: Chiara Cavazzin (until October 2013), Daniela Corno
(until November 2013), Vasco Meneghini
PHD STUDENTS: Giacomo Frati, Annalisa Lattanzi (until March 2013),
Alessandra Ricca
TECHNICIANS: Luigi Tiradani (since November 2013)
Gene therapy for WASP/Omenn Unit –––––––––––––––––––––––––––––––––––––––––––––––––––– 122
HEAD OF UNIT: Anna Villa
POST-DOCTORAL FELLOWS: Ileana Bortolomai, Marita Bosticardo, Maria Carmina Castiello
PHD STUDENT: Lucia Sereni
TECHNICIAN: Elena Draghici
Gene transfer into stem cells Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––– 122
HEAD OF UNIT: Giuliana Ferrari*
RESEARCHERS: Maria Rosa Lidonnici**, Francesca Salvatori
PHD STUDENTS: Annamaria Aprile, Ylenia Paleari**
TECHNICIANS: Giacomo Mandelli, Claudia Rossi, Francesca Tiboni
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DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Research Units, HSR-TIGET
Hematopoietic stem cell based gene therapy for lysosomal storage –––––––––––– 123
disorders Unit
GROUP LEADER: Alessandra Biffi
POST-DOCTORAL FELLOWS: Alessia Capotondo, Francesca Cecere, Martina Cesani, Ilaria
Visigalli
PHD STUDENTS: Stefania Delai, Rita Milazzo**, Silvia Ungari**
FELLOWS: Eleonora Cavalca, Francesca Ferro, Daniela Redaelli
TECHNICIAN: Serena Acquati
Immunological tolerance Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 123
HEAD OF UNIT: Maria Grazia Roncarolo*
POST-DOCTORAL FELLOW: Andrea Annoni
PHD STUDENT: Mahzad Akbarpour
TECHNICIANS: Grazia Andolfi, Eleonora Tresoldi (until September 2013)
Genetic autoimmune diseases ––––––––––––––––––––––––––––––––––––––––––––––––––––– 124
GROUP LEADER: Rosa Bacchetta
POST DOCTORAL FELLOWS: Laura Passerini, Francesca Santoni De Sio**
PHD STUDENT: Eva Rossi Mel**
RESIDENT: Federica Barzaghi**
TECHNICIANS: Silvia Restelli , Claudia Sartirana
Pathogenesis and therapy of ADA-SCID Unit –––––––––––––––––––––––––––––––––––––––––– 125
HEAD OF UNIT: Alessandro Aiuti
POST-DOCTORAL FELLOWS: Luca Biasco, Immacolata Brigida, Aisha Vanessa Sauer,
Samantha Scaramuzza
PHD STUDENTS: Nicola Carriglio, Maddalena Migliavacca, Serena Scala**
TECHNICIANS: Cristina Baricordi (until April 2013), Luca Basso Ricci, Francesca Dionisio,
Stefania Giannelli, Raisa Jofra Hernandez, Michela Vezzoli (since October 2013)
Safety of gene therapy and insertional mutagenesis Unit –––––––––––––––––––––––––– 126
GROUP LEADER: Eugenio Montini
POST-DOCTORAL FELLOWS: Andrea Calabria, Daniela Cesana, Marco Ranzani
PHD STUDENT: Monica Volpin**
FELLOWS: Stefano Annunziato, Laura Rudilosso
TECHNICIANS: Fabrizio Benedicenti, Pierangela Gallina, Erika Tenderini
BIOINFORMATICIANS: Stefano Brasca, Giulio Spinozzi
Tolerogenic dendritic cells Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 126
GROUP LEADER: Silvia Gregori
PHD STUDENTS: Giada Amodio**, Michela Comi, Monica Gianolini, Grazia Locafaro
TECHNICIANS: Fabio Russo, Daniela Tomasoni
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Clinical Research Units
PCRU - Pediatric Clinical Research Unit –––––––––––––––––––––––––––––––––––––––––––––––– 127
HEAD OF UNIT: Alessandro Aiuti
PROJECT LEADERS: Maria Grazia Roncarolo* and Alessandro Aiuti (ADA-SCID; WAS),
Maria Sessa and Alessandra Biffi (MLD)
PHYSICIAN: Maria Pia Cicalese
RESIDENTS: Francesca Ferrua**, Marta Frittoli**, Mila Kalapurackal (since July 2013)**,
Laura Lorioli**, Sara Napolitano**, Roberta Pajno**
TCTO COORDINATOR: Luciano Callegaro
REGULATORY AFFAIRS: Marco Bonopane, Antonio Martelli
RESEARCH NURSES: Gigliola Antonioli, Miriam Casiraghi
DATA MANAGERS: Laura Castagnaro (since November 2013), Sara Di Nunzio (until
September 2013), Marcella Facchini (since November 2013), Emanuela Mrak (since
October 2013)
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
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DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Introduction by the Directors
Mission and Vision - The mission of the Division of Regenerative Medicine, Stem Cells and Gene Therapy is to develop novel cell and gene therapy strategies for immuno-hematologic, metabolic, muscle and
neuro-degenerative diseases and cancer. By bringing together researchers with complementary expertise, it enables effective synergy between projects that share common methodological approaches and
face similar scientific/technological and regulatory hurdles.
Organization - The Division comprises three major pillars. The first pillar is the San Raffaele-Telethon Institute for Gene Therapy (HSR-TIGET). This is a multi-disciplinary research Institute with an established
leadership in the development of gene and cell therapy strategies and their application to the treatment
of inherited immuno-hematologic and metabolic diseases. The second pillar embraces basic and translational research on genetic and cellular mechanisms of muscle development, repair and regeneration in
response to inherited dystrophies, inflammatory and vascular disease. The third pillar is the clinical
Hematopoietic Stem Cell (HSC) Transplantation Unit, which has one of the largest case records in EU,
and the Experimental Hematology and Functional Immunogenetics Units, which have long been engaged
in innovative immunotherapy approaches for hematologic malignancies. The governance is implemented
by Luigi Naldini, Director, and Fabio Ciceri, co-Director.
Goals - The Division hosts internationally recognized basic and translational research with the following
goals: isolate, characterize and devise improved transplantation strategies for stem and progenitor cells
from the hematopoietic, muscle and nervous system; unravel the genetic bases and molecular pathogenesis of immunodeficiencies and autoimmune diseases, lysosomal storage diseases and muscular
dystrophies; develop new gene transfer and gene editing strategies for treating genetic diseases as well
as for the immunotherapy of cancer based on genetic engineering of T-cell specificity against tumor-associated antigens or targeted progenitor based therapy; investigate the role of angiogenesis, inflammation and immune responses in modulating regeneration of diseased tissues, engraftment of transplanted
cells, survival of gene-corrected cells and response of tumors to immunotherapy. The clinical units translate preclinical studies into innovative clinical trials and develop novel readouts to monitor disease progression and response to therapy.
Main Achievements - Three new first-in-human phase I/II trials are active: two are among the first ever to
exploit lentiviral vectors for HSC gene transfer and aim to the treatment of Metachromatic Leukodystrophy and Wiskott-Aldrich Syndrome; the third is the first cell therapy using mesangioblasts for Duchenne
Muscular Dystrophy. All trials have treated several patients and report no serious adverse event related
to the therapy. Major clinical benefits have been observed in all MLD and WAS patients together with substantial levels of stable long term genetic engineering of reconstituted hematopoiesis. Mesangioblast therapy has proven safe and able to reconstitute some dystrophin expression in vivo. A major alliance with
GlaxoSmithKline is helping TIGET to translate its pioneering HSC-based gene therapies into novel medicines to be made available worldwide. In translational research, a surface signature was identified for
CD4 type 1 T regulatory (Tr1) cells. It was also shown that FOXP3 gene transfer into CD4+ T cells convert them into T(reg) cells displaying stable phenotype and suppressive function. The use of the new surface markers and gene transfer strategies makes it feasible to purify regulatory T cells for cell therapy to
induce or restore tolerance in subjects with immune-mediated diseases. New chimeric antigen receptors
have been tested for genetically redirecting T-cell specificity against tumors and used in the context of innovative gene transfer platforms to broaden the reach of adoptive immunotherapy of cancer. A new insertional mutagenesis platform based on lentiviral vectors was developed to discover oncogenes and
allowed identifying new genes associated with hepatocellular carcinoma in human cancer.
Training opportunies - Graduate and Ph.D. programs, post-doctoral fellowships and clinical residency.
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Research Units
Angiogenesis and tumor targeting Unit
Exploiting tumor-infiltrating monocyte/macrophages to fight tumors
Tumor-infiltrating hematopoietic cells play important and sometimes contrasting biological roles
within the tumor. We previously characterized,
both in mice and humans, a subset of tumor associated monocyte/macrophages (TAMs) that express the Angiopoietin receptor TIE2 and are
specifically recruited to tumors (Tie2-expressing
monocytes, TEMs). Selective elimination of TEMs
inhibits angiogenesis and tumor growth in several
mouse tumor models. We thus hypothesized that
genetic engineering of hematopoietic stem cells
(HSC) with anti-tumor transgenes transcriptionally
targeted to TEMs could provide a novel gene
therapy strategy to treat tumors. Using a combination of transcriptional and microRNA-mediated
control, we achieved selective expression of an
interferon-α (IFN-α) transgene in the monocyte
progeny of engineered HSC transplanted into
mice. The regulated IFN-α transgene did not impair engraftment and long-term multilineage repopulation. By applying our strategy to mouse
breast cancer models, we achieved inhibition of
tumor progression and experimental metastases
through enhanced generation of effector T cells
and their recruitment to the neoplastic tissues. By
forcing IFN-α expression in tumor-infiltrating
macrophages, we blunted their innate pro-tu-
moral activity and reprogrammed the tumor microenvironment towards more effective dendritic
cell activation and immune effector cell cytotoxicity. In a parallel study, we investigated the role of
miR-155 in TAMs, as miR-155 upregulation in
hematopoietic cells has been implicated in the
deployment of effective innate and adaptive immunity. We stably knocked down (KD) miR-155 in
the myeloid compartment of a mouse model of
spontaneous breast carcinogenesis. Notably,
miR-155/KD significantly accelerated tumor
growth by impairing classical activation of TAMs.
This created an imbalance towards a pro-tumoral
microenvironment as evidenced by a lower proportion of CD11c+ TAMs, reduced expression of
activation markers and skewing of immune cells
within the tumor towards an M2/Th2 response.
This study highlights the importance of tumor infiltrating hematopoietic cells in constraining carcinogenesis and establishes an anti-tumoral function
of a prototypical oncomir (Zonari et al., Blood
2013). Overall, our studies illustrate the biological
complexity of tumor infiltrating myeloid cells, some
of which constrain while other promote carcinogenesis, and highlight new therapeutic strategies
to manipulate these cells to treat tumors.
Luigi Naldini
Functional genetics of muscle regeneration
Vascular progenitors fate and role during muscle development and
regeneration
Regeneration of muscle fibers, lost during pathological muscle degeneration or after injuries, is
sustained by generation of new myofibers, Progenitors in the muscle comprise quiescent myogenic cells, the satellite cells, that are primary
stem cells responsible for skeletal muscle regeneration after damage and vessel-associated progenitors, such as the mesoangioblasts (MAB).
Using a genetic lineage tracing approach, a transgenic mouse expressing an inducible Cre under
the control of an endothelial specific promoter we
have provided new insights on the distinctive
characteristics of the extraembryonic and embryonic hemogenic endothelium and we have identified for the first time the in vivo counterpart of embryonic MAB (Azzoni et al., Development, in
press).
We have also been studying the relationship be-
tween the innate immune system and muscle and
vascular progenitors during acute and chronic
muscle regeneration progenitors. We have shown
that the Nitric Oxide donor molsidomine can modulate the characteristics of the macrophages that
infiltrate the dystrophic muscle, enhancing their
healing function and reducing fibrosis (Zordan et
al, European Journal of Pharmacology 2013; Rovere-Querini et al, 2013, European Journal of
Pharmacology 2013). We have also shown that
macrophages are necessary for efficient vascular
remodeling in the injured muscle. When phagocyte infiltration is compromised endothelial-derived progenitors undergo a significant endothelial
to mesenchymal transition (EndoMT). This together with an inefficient tissue remodeling contributes
to the accumulation of collagen, fat and significant
fibrosis. Our findings provide new insights in En113
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Research Units
doMT in the adult skeletal muscle, and suggest
that endothelial cells in the skeletal muscle may
represent a new target for therapeutic intervention
in fibrotic diseases (Zordan et al, Cell Death and
Disease in press).
Silvia Brunelli
Neural stem cell biology
Glioblastoma multiforme (GBM) is the most common and malignant brain tumor of adults. GBM
comprise subpopulations of cancer stem cells
(CSCs) that can generate experimental gliomas,
characterized by an infiltrative growth pattern, typical of the human disease. By comparing the transcriptome of invasive GBM CSCs vs. non-invasive serum-grown glioma cell lines, we identified
two candidate genes that actively promote GBM
invasion and angiogenesis, in vivo. We are currently defining their role by modulating their expression through gain-of-function and loss-offunction strategies and interfering with the activation of molecular pathways involved in their function.
Medulloblastoma (MB) arises from mutations in
stem/progenitor cells located in restricted hindbrain territories. To identify novel molecular mediators involved in medulloblastomagenesis, we
compared distinct types of postnatal hindbrainderived neural stem cells (NSCs) with compound
Ptch/p53 mutant MB CSCs, which faithfully phenocopy the different variants of human MB in vivo.
Transcriptome analysis of hindbrain NSCs and
MB CSCs resulted in the generation of well-defined gene signatures, each reminiscent of a spe-
cific human MB molecular subclass (Corno et al.,
Cancer Discovery, 2012). From these signatures,
we selected top-ranking genes and looked for
miRNAs regulating all of them at the same time.
We have now clearly defined the expression and
function of one specific candidate miRNA, which
acts as tumor suppressor miRNA in vivo by inhibiting the expression of an oncogene that was
never implicated previously in medulloblastomagenesis.
Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder characterized by hamartomatous neurological lesions that exhibit abnormal cell proliferation and differentiation. mTOR
pathway hyperactivation by mutations in either
Tsc1 or Tsc2 genes underlies TSC pathogenesis.
We deleted Tsc1 in both embryonic neuroepithelial progenitors (NEPs) as well as radial glial cells
(RGCs) and found that mutant mice faithfully recapitulated TSC neuropathological lesions (Magri et
al., Cell Stem Cell, 2011; Magri et al., Disease
Models & Mechanisms, 2013). We are currently
generating additional mouse models of TSC by
neural stem cells (NSC)-restricted inducible conditional mice.
Rossella Galli
Autoimmunity & vascular inflammation Unit
Inflammation encompasses diverse events that
are required to eradicate invading pathogens and
to repair injured tissues. Despite its homeostatic
function, unyielding inflammation shapes the clinical features and determines the persistence of
most diseases of higher vertebrates. Unrelenting
inflammation often depends on defects in the initiation and in the execution of cell death programs.
In particular the clearance of cell debris and the
activation of autophagic pathways appear as crucial players in the pathogenesis of systemic autoimmune and rheumatic diseases, in which they
behave as initiators and amplifying circuits. Stem
and precursor cells represent a preferential target
of the autoimmune response, which in turn jeopardize their ability to regenerate injured tissues.
Vascular inflammation fulfills homeostatic roles
and humoral innate immunity finely tunes the
cross-talk among circulating leukocytes, platelets
and endothelial cells. We are investigating the
molecular mechanisms underlying the vicious circle that maintains and amplifies vessel and tissue
injury, with specific attention to the role of injuryassociated signals (Damage-Associated Molecular Patterns, DAMPS) and of acute phase proteins
as environmental cues that transform regenerating cells in a trigger for self-sustaining autoimmune responses. Our recent work has allowed
identifying a self-sustaining circuit by which the
cross-talk between platelets and leukocytes in
Systemic Sclerosis regulate the oxidation state
and the inflammatory action of the prototypical
DAMP, HMGB1, contributing to the generation of
Neutrophil Extracellular Traps (NETs) and to the
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
persistence of vascular inflammation. Conversely,
the ability of endogenous HMGB1 to recruit
leukocytes and to modify the function of endothelial cells and pericytes contributes to various fea-
tures of dermatomyositis and to sustain the
growth and the spreading of neoplastic lesions
within the peritoneal cavity.
Angelo A. Manfredi
Figure 17. HMGB1 as well as RAGE agonist induce the formation of neutrophil extracellular traps.
Innate immunity and tissue remodelling
The response of tissues to injury: macrophages are in control
Macrophages play various roles in damaged tissues: they amplify local injury, either directly or indirectly, and they favor remodelling and repair. To
break the molecular code by which macrophages
shape the tissue response to microbial or sterile
stressful events, which can be partially mimicked
or tampered with, will provide novel strategies for
the treatment of a variety of human diseases. We
focus on the events that determine the action of
infiltrating polarized macrophages in experimental
models of acute and chronic injury of skeletal
muscle (inflammatory myopathies and muscular
dystrophies). Moreover, we are interested in the
role of the innate immune responses in shaping
the interaction between the mother and the developing embryo, with specific attention to pregnancy complications. During the last year we have in
particular focused on the dissection of molecular
events that are involved in the physiopathologic
actions of macrophages in the remodeling tissue,
specifically the regulation of the nitric oxide synthase expression and of the ability to provide iron
to nascent myofibers. Moreover we have been involved in the dissection of the mechanisms by
which low molecular weight heparin influences
specific features of the innate immune responses
in patients with high-risk pregnancies.
Patrizia Rovere-Querini
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DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Research Units
MHC -IIA
MHC -IIB
MHC -I
Figure 18. Extensorium Digitorum Longus (EDL) mouse muscle staining for the different Myosin Heavy Chain
(MHC) isotypes. Type I (blue) are oxidative fibers, Type IIA (green) have both oxidative and glycolitic metabolism,
while Type IIB (red) are glycolitic fibers.
Experimental hematology Unit
Cancer immunotherapy with genetically engineered T lymphocytes
Cancer immunotherapy aims at harnessing the
power and specificity of the immune system, well
documented by its ability to combat infectious
pathogens, to treat cancer. This approach has
been limited, for several years, by a combination
of biological and technological factors, including
immune escape mechanisms adopted by tumors, the lower immunogenicity of cancer cells
compared to infectious pathogens and pre-existing tolerance toward tumor-associated (TAA), but
often not tumor-specific, antigens. We exploit
gene transfer techniques to overcome these limitations and to generate long lasting tumor-reactive
T lymphocytes to treat patients affected by hematological malignancies (Cieri Immunol. Rev. 2013).
1. Memory T cells with stem cell-like properties in
health and disease.
The ability to remember and respond more robustly in a second encounter with a pathogen is a
critical property of the adaptive immune system.
This process has been proposed to involve a
stem cell-like memory T-cell subset (TSCM), able
to rapidly differentiate in effectors and self-renew
upon antigen re-encounter. We identified conditions to genetically modify and expand long-living
TSCM with the ability to self renew and the plas-
ticity to differentiate into potent effectors. (Cieri et
al., Blood 2013).
2. Suicide gene therapy in allogeneic stem cell
transplantation.
The transfer of a suicide gene into donor lymphocytes promotes rapid and effective immune reconstitution and control of GvHD. Building on clinical results of suicide gene therapy trials, we are
currently designing innovative approaches of T
cell manipulation designed to potentiate the graftversus-leukemia effect of donor lymphocytes (Casucci et al., Mol. Ther. 2013).
3. TCR gene editing
To completely and permanently substitute T cell
specificity, we developed the TCR gene editing
approach based on: i. Somatic knockout of the
endogenous TCR genes (by transient exposure to
α and/or β chain specific Zinc Finger NucleasesZFN), and ii. Introduction of a tumor-specific TCR
by lentiviral vectors. This approach, was validated
in vitro and in vivo with different TCRs specific for
antigens expressed by acute leukemias and multiple myelomas (Provasi, Genovese, et al., Nat.
Med 2012).
Chiara Bonini
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Gene expression and muscular dystrophy Unit
The Gene Expression and Muscular Dystrophy
Unit is interested in understanding the regulation
of muscle-specific gene expression. We are
studying this in normal physiology and in disease
using FSHD muscular dystrophy as a paradigm.
FSHD is the second most common muscular
dystrophy in adults. It is an autosomal dominant
disorder that is not due to a mutation within a protein-coding gene. Instead, FSHD patients carry
deletions of 3.3 kilobase macrosatellite repeats,
termed D4Z4, located at chromosome 4q35.
During 2013, we investigated the biology and
mechanism of action of the FSHD candidate
gene FRG1.
We showed that FRG1 is selectively overexpressed in FSHD patients. Accordingly, FRG1
transgenic mice develop a muscular dystrophy
with physiological, histological, ultra structural and
molecular features analogous to FSHD patients.
We have also shown that the transcriptome of
FRG1 mice is remarkably similar to that of FSHD
patients, further supporting a role for FRG1 in the
disease and validating our animal model.
We showed that FRG1 primarily inhibits the acti-
vation, clonogenic and differentiation of myogenic
stem cells. In classical muscular dystrophies,
myogenic stem cells are affected late in the disease as a secondary effect of muscle wasting.
On the contrary, our data suggest that defects in
myogenic stem cells could be at the basis of
FSHD.
We have shown that FRG1 operates through two
molecular mechanisms: reduced expression of
the splicing factor Rbfox1 and interference with
the activity of the epigenetic repressor Suv420h1. Among extra-muscular manifestations of
FSHD are mental retardation, epilepsy and
autism. Interestingly, RBFOX1 mutation or downregulation is also associated to the same symptoms identifying a potential mechanism for the
neurological involvement in FSHD.
Collectively, our results provided a long awaited
molecular explanation for the muscle differentiation defects that have been frequently reported in
FSHD and identified molecular pathways and
FRG1 targets altered in FSHD that can be exploited for therapeutic purposes.
Davide Gabellini
Figure 19. Transplantation of muscle stem cells during muscle regeneration in mice. Laminin (red), Hoechst (blue)
and transplanted muscle stem cells (green) staining of tibialis anterior cryosections, 10 days after muscle injury.
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DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Research Units
Leukemia immunotherapy Unit
The Leukemia Immunotherapy Group led by Dr.
A. Bondanza is actively engaged in the development of novel gene therapy strategies that can be
readily translated to the clinic for the treatment of
hematological malignancies and, possibly, solid
tumors.
The main focus is on chimeric antigen receptor
(CAR)-modified T cells, i.e. T cells modified with a
synthetic receptor that combines the antigenbinding moiety of a monoclonal antibody with the
signal transduction machinery of a T cell. In this
endeavor, the Group takes advantage of cuttingedge gene transfer technologies available within
the Division and innovative humanized mouse
models originally developed over the last few
years (Bondanza et al, Blood 2006 & 2011,
Kaneko et al, Blood 2009). During 2013, a CAR
specific for the tumor-initiation antigen CD44v6
has been developed and preclinically validated for
the treatment of acute myeloid leukemia and multiple myeloma (Casucci et al, Blood 2013). Moreover, different novel CAR targets have been identified. In parallel, the Group researches for elucidating the anti-inflammatory and regenerative
properties of mesenchymal stromal cells from different sources (bone marrow, adipose tissue,
cord blood) with the final aim of identifying critical
factors and over-expressing them by genetic
means for the treatment of human diseases (graftversus-host disease, autoimmunity).
Finally, the Group is engaged in a wide European
project (TRANSCAN Haploimmune) on the validation of immune biomarkers predictive of clinical
outcome after allogeneic hematopoietic stem cell
transplantation for leukemia.
Attilio Bondanza
Molecular and functional immunogenetics Unit
The scientific activity of this Unit is aimed at characterizing the biological bases of the interplay between immune system and leukemia in the context of allogeneic hematopoietic stem cell transplantation (HSCT).
During the year 2013, the following main achievements were made:
• we retrospectively evaluated 233 transplants to
determine the incidence, risk factors and clinical
outcome of leukemia relapses with genomic
loss of the mismatched HLA. HLA loss variants
accounted for 33% of the relapses after family
donor HSCT and were significantly associated
with disease aggressiveness and clinical manifestations of graft-versus-host alloreactivity, further suggesting their relevance as a mechanism
of immune evasion and warranting their routine
screening after transplant (Crucitti et al., submitted);
• we developed an innovative diagnostic tool
based on quantitative PCR (qPCR) for the early
detection of HLA loss relapses, and validated it
in our translpant series (Vago et al., in preparation);
• by using an innovative system, we dissected
the molecular bases of T cell recognition of
HLA-DPB1 alleles, demonstrating the relative
impact of individual amino acids on alloreactivity
patterns, and by this defining the “functional distance” amongst HLA-DPB1 alleles, a promising
tool to evaluate the permissiveness of HSCT
mismatches (Crivello et al., submitted);
• by comparing the mRNA expression profile of
patients’ leukemic cells harvested at diagnosis
and at relapse after allogeneic HSCT we
demonstrated in the latter the selective deregulation of immune-related processes, comprising
antigen processing and presentation and T cell
costimulation, and functionally validated that
these mechanisms concur in prompting
leukemia immune evasion from donor-derived
immunity (Toffalori et al. in preparation);
• by combining immunogenetic and next-generation sequencing analyses, we deciphered the
complex disease history of a patient with
leukemia experiencing subsequent relapses upon serial treatments. We documented radical
changes in the disease genetic features at each
presentation, selectively evolving to escape
from therapies, and throughout these changes
identified leukemia founder mutations, which
were tracked back to pre-leukemic precursors
(Vago et al., in preparation).
Fabio Ciceri
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Clinical Research Units
Hematology and hematopoietic stem cell transplantation Unit
The Unit is developing transplantation from partially HLA-incompatible (haploidentical) family members
to offer a cure to all patients affected by high-risk
hematologic malignancies who are candidate to allogeneic Hematopoietic Stem Cell Transplantation. Over the last years, we developed both T-cell
depleted and T-cell replete platforms for haploSCT.
Extensive application of T-cell depletion is limited by
high rate of late transplant related mortality (TRM) and
relapse associated with the inadequate immune reconstitution (IR) due to ex vivo T cell depletion or in
vivo post-transplant cyclophosphamide administration for severe graft-vs-host disease (GvHD) prevention. We extensively developed HSV-TK+ suicide
gene donor lymphocytes after haploidentical transplantation (haplo-HSCT). A phase III trial (TK008,
NCT00914628) is ongoing in 8 centres in Europe
and US and preliminary results confirm safety and
potential benefit in improving survival of the T-cell
gene transfer technology integrated with T-cell depleted haplo-HSCT
We developed unmanipulated peripheral blood
stem cells haploSCT by exploring a calcineurin inhibitor-free rapamycin-based GvHD prophylaxis
regimen (TrRaMM study, Eudract 2007-5477-54). We
showed that rapamycin allowed the preferential expansion of donor-derived natural T regulatory cell
(Tregs), ultimately protecting from the severe GvHD
that would have been expected in this context.
Building on this promising experience, we are currently
testing several new rapamycin-based regimens to improve the efficacy and feasibility of haploidentical
HSCT. In more than fifty patients with high-risk malignancies we combined a treosulfan- and fludarabinebased chemotherapeutic regimen to low-dose Total
Body Irradiation (4Gy TBI) modulating in vivo T cell depletion with ATG-Fresenius on the basis of donor-recipient matching and underlying disease risk (TrRaMM4Gy study, Eudract 2011-001534-42).
Specific effort is dedicated to the biological characterization of immune reconstitution, comprising the
detailed analysis of the early and late immune events.
Cell therapy of DMD by intra-arterial delivery of
HLA-identical allogeneic mesoangioblasts (MABs)
Five pediatric patients were treated (age: 8-12
years) at our Institution.
Fabio Ciceri
Immunohematology and transfusion medicine Unit
The Hospital San Raffaele (OSR) Immunohematology and Transfusion Medicine Service (ITMS) provides clinical services to support OSR patients in
need of blood component therapy, cellular therapy,
therapeutic apheresis, and specialized laboratory diagnostics. This ISO 9002 Certified unit collects and
prepares the blood components and cellular therapy products used in patient care at the OSR, maintain an accredited Immunohematology Reference
Lab and provides education in the field of Transfusion Medicine. ITMS is conducting a project, funded by Regione Lombardia, on the appropriateness
of blood transfusion.
The ITMS is subdivided into two distinct subunits,
each responsible for a particular process:
Blood Donation Center
The blood donation center subunit is responsible for
the collection and testing of blood to be transfused
into patients at the San Raffaele Hospital. It is responsible for handling all aspects of donor recruitment for whole blood products, apheresis products,
the auto-transfusion program and therapeutic phlebotomy. During 2013 were presented to make a donation 8424 candidates of these only 6820 have donated. 5535 were donations of whole blood and the
rest were donations by apheresis, plateletpheresis
or plasmapheresis.
Therapeutic Apheresis and Cellular Therapy
The Therapeutic Apheresis and Cellular Therapy subunit is responsible for collecting and processing
hematopoietic stem cells and performs the necessary diagnostic testing required for bone marrow
transplantation procedures. The lab supplies
hematopoietic stem cells and relevant cells in support of clinical trials for allogenic bone marrow and
peripheral blood transplantation and offers a Stem
Cell Cryo Banking service for autologous and allogeneic bone marrow products. Bone Marrow from
qualified donors is collected in accordance and
recognition of the Italian Bone Marrow Donor Registry (IBMDR). Therapeutic apheresis procedures to
treat patients with neurologic and blood diseases,
including photopheresis, red cell and plasma exchange procedures are also performed routinely.
The unit of therapeutic apheresis is part of the bone
marrow transplants program and underwent Jacie
Accreditation Inspection in October 2013.
During 2013, were performed 212 apheresis for the
collection HSCT.
Fabio Ciceri
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DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Introduction by the Director
HSR-TIGET
The San Raffaele Telethon Institute
for Gene Therapy
The San Raffaele-Telethon Institute for Gene Therapy (HSR-TIGET) is a joint-venture between the San Raffaele Scientific Institute and the Telethon Foundation established to perform research on gene transfer and
cell transplantation and translate its results into clinical application of gene and cell therapy for genetic diseases. The research projects aim to: a) identify the genetic bases and pathophysiology of primary immunodeficiencies and autoimmune disorders, leukodystrophies and other lysosomal storage disorders
and thalassemia; b) develop new gene transfer and editing technologies for efficient and safe genetic correction of disease ex vivo and in vivo; c) characterize the biological properties of stem cells and establish
procedures for their isolation, genetic modification and transplantation; d) investigate cell types mediating innate and adaptive immunity and modulate the immune response to gene and cell products to improve efficacy and stability of the therapy. The gene and cell therapy strategies being developed are then
tested in pre-clinical disease models under GLP conditions within the TIGET “Centro di Saggio” in preparation for clinical trials. The clinical studies are conducted within the TIGET Clinical Research Unit, which
is devoted to the diagnosis, treatment and follow-up of patients with primary immunodeficiencies, hematologic and metabolic disorders, in close collaboration with the Pediatric Immunohematology Unit, the
Bone Marrow Transplantation Unit, and the GMP Facility of MolMed SpA.
TIGET pioneering gene therapy of a severe form of primary immunodeficiency (ADA-SCID) has provided
the most successful demonstration today that gene transfer into human hematopoietic stem cells (HSC)
can safely result in long-term disease correction. This therapy is now undergoing development for drug
registration by GlaxoSmithKline (GSK) and is expected to become the first ex vivo gene therapy product
on the market. We also made essential contributions to the development of lentiviral vectors, which have
become one of the most widely used tool in biomedical research today. Since 2010 TIGET has been conducting two first-in-human trials of lentiviral vector mediated HSC gene therapy for Metachromatic
Leukodystrophy and Wiskott-Aldrich syndrome. Several patients have already been safely treated in each
trial and continue to show stable and remarkably high levels of hematopoietic reconstitution with gene corrected cells and evidence of major therapeutic benefit. The molecular and clinical results observed in the
first 3 patients treated in both trials were reported in 2 back to back full research articles in the Science
magazine on August 2013 and were deeply covered by the scientific and lay press and news agencies
worldwide. At the end of 2013, GSK exercised its rights of option on these two other TIGET gene therapies and has since embarked in their development towards drug registration. In parallel, we are investigating the pathophysiological mechanisms leading to immune dysfunction and autoimmunity in primary
immunodeficiencies, or underlying disease correction in leukodystrophies, such as microglia turnover,
enzyme overexpression and biodistribution to the CNS. In these neurodegenerative diseases, we are
also investigating the potential of intra-CNS gene delivery and neural stem cell transplantation. We continue to improve vector design by limiting the impact on cellular transcription and exploiting microRNA regulation to stringently control transgene expression. Improvements are validated by sensitive in vivo models
to score genotoxicity and high-throughput vector integration site analyses to monitor clonal behaviour of
vector-transduced cells in experimental models and in the clinical trial patients. HSC biology is investigated
to identify novel regulators of cell growth and quiescence, such as microRNAs, that help designing better strategies for ex vivo expansion, genetic modification and transplantation. Meanwhile, new gene targeting and editing approaches are developed based on artificial endonucleases, such as Zinc Finger
Nucleases, TALENs and Crispr/Cas9 RNA-guided nucleases, which brings the possibility of targeted integration, gene editing and correction of mutations within the reach of gene therapy. The potential of in
vivo gene delivery is investigated to treat hemophilia, exploiting a lentiviral platform stringently targeted to
hepatocytes by transcriptional and microRNA-regulated control. By using this strategy, we could overcome
the immunological barrier to in vivo gene transfer and establish long-term correction of hemophilia in small
and large animal models and induce active tolerance to the transgene products. In parallel, significant advances were made in the field of immunological tolerance mediated by regulatory T cells and the potential application of these cells as cell therapy of immune-mediated diseases.
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Research Units, HSR-TIGET
Gene transfer technologies and new gene therapy
strategies Unit
Our research has long been investigating new
strategies to improve the therapeutic reach, efficiency and safety of gene transfer. Over the years
we have developed a versatile gene transfer platform based on lentiviral vectors (LV), which has
become one of the most widely used tool in biomedical research and has recently entered clinical
testing in T-cell and Hematopoietic Stem Cells
(HSC)-based gene therapy. In 2013, we reported
the results of two first-in-human clinical trials of
LV-mediated HSC gene therapy undergoing in our
Institute for the treatment of two rare inherited diseases, metachromatic Leukodystrophy (MLD)
and Wiskott-Aldrich syndrome (WAS). All treated
patients showed stable and high levels of polyclonal gene marking and therapeutic gene expression in the reconstituted hematopoiesis with
remarkable therapeutic benefit. Data from both trials support the feasibility and safety of extensive
genetic engineering of human hematopoiesis, essentially producing a stable “transgenic”
hematopoietic system in humans (Biffi et al., Science, 2013; Aiuti et al., Science 2013). These
encouraging results offer the perspective of a
treatment for MLD and WAS and open the avenue to develop new therapeutic strategies for
other diseases. LV, however, integrate semi-randomly in the genome, which leads to variegated
transgene expression and is associated with insertional mutagenesis, the risk of which has been
substantially alleviated by improved vector design
but cannot be fully abrogated. We have shown
that artificial nucleases, such as engineered Zinc
Finger Nucleases (ZFN) can be used to edit specific gene sequences. We are exploiting this strategy for targeted integration of transgenes at preselected and safe genomic sites and for in situ
correction of inherited mutations in human cells,
which allows restoring both gene function and
physiological expression. Concerning transgene
expression control, we have shown that endogenous microRNA can be exploited to stringently
regulate transgene expression and target it to desired cell types (Amendola et al, Mol Ther 2013).
We are exploiting miR-126 to improve the safety
and efficacy of HSC gene therapy. By making LV
responsive to miR-126 we can suppress transgene expression in HSC, sparing them from potential toxicity, and target it to selected lineages of
differentiated progeny. MiR-regulated LV are also
being exploited for liver gene transfer. Using
miR142-regulated hepatocyte-targeted LV we
have established long-term Factor IX expression
in mouse and dog models of hemophilia B. We
now showed that this strategy can eradicate preexisting anti-FIX antibodies and inhibitors in hemophilia B mice and induce active tolerance in an already primed immune system (Annoni*, Cantore*
et al., EMBO Mol Med 2013). These data position
gene therapy as an attractive treatment option also for inhibitors-positive hemophilic patients.
Luigi Naldini
Gene/Neural stem cell therapy for lysosomal storage
diseases
Leukodystrophies are genetic neurodegenerative
pediatric disorders that affect the CNS, PNS and
visceral organs. Gene/cell therapy strategies are
promising approaches for the treatment of the
CNS pathology in leukodystrophies, as they have
the potential to provide a permanent source of the
deficient enzyme. Our previous studies demonstrated that neonatal intracerebral delivery of a
therapeutic vector, intracerebral transplantation of
neural stem cells (NSCT) and hematopoietic cell
transplantation (HCT) are safe and effective as independent treatments in preventing/delaying
pathology in relevant mouse models of leukodystrophies.
Interestingly, we have substantial evidence that a
combinatorial strategy based on NSC gene therapy (GT) or intracerebral GT coupled to HSC transplant, is safe and effective in providing relevant
and timely enzymatic levels in all the affected organs, providing benefits when compared to single
treatments in terms of amelioration of pathology
and enhancement of survival. In order to scale up
these approaches to larger brains, we have tested the feasibility and tolerability of the intracerebral
GT platform in juvenile non-human primates
(NHP). Our preliminary data show robust biodistribution of vector and transgene in animals injected
with a LV.ARSA. We are now addressing potential
safety concerns. Finally, a better knowledge of the
pathogenesis of LSD is instrumental to develop
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DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Research Units, HSR-TIGET
effective therapies. We have established a collection of induced pluripotent stem cells (iPSCs) derived from the somatic reprogramming of normal
donor and patients affected by Metachromatic
and Globod Leukodystrophy (MLD, GLD) that we
have characterized for their bona fide pluripotency. We have optimized a protocol to obtain iPSCderived neural stem/progenitor cells to be used
as a renewable source of patient-derived neural
cells that will be further differentiated in cultures
enriched in oligodendrocytes and mature neurons. These cultures will offer an unprecedented
opportunity to recapitulate the LSD CNS pathology in vitro and to test gene/cell replacement
strategies.
Angela Gritti
Gene therapy for WASP/Omenn Unit
Wiskott-Aldrich Syndrome protein deficiency perturbs the homeostasis of
B-cell compartment in humans
Wiskott-Aldrich Syndrome protein (WASp) regulates the cytoskeleton in hematopoietic cells and
mutations in its gene cause the Wiskott-Aldrich
Syndrome (WAS), a primary immunodeficiency
with microthrombocytopenia, eczema and a higher susceptibility to develop tumors. Autoimmune
manifestations, frequently observed in WAS patients, are associated with an increased risk of
mortality and still represent an unsolved aspect of
the disease. B cells play a crucial role both in immune competence and self-tolerance and defects in their development and function result in
immunodeficiency and/or autoimmunity. We performed a phenotypical and molecular analysis of
central and peripheral B cell compartments in
WAS pediatric patients. We found a decreased
proportion of immature B cells in the bone marrow
correlating with an increased presence of transitional B cells in the periphery. These results could
be explained by the defective migratory response
of WAS B cells to SDF-1α, essential for the retention of immature B cells in the BM. In the periphery, we observed an unusual expansion of
CD21−/low B cell population and increased plasma BAFF levels that may contribute to the high
susceptibility to develop autoimmune manifestations in WAS patients. WAS memory B cells were
characterized by a reduced in vivo proliferation,
decreased somatic hypermutation and preferential usage of IGHV4-34, an immunoglobulin gene
commonly found in autoreactive B cells.
In conclusion, our findings demonstrate that
WASp-deficiency perturbs B cell homeostasis
thus adding a new layer of immune dysregulation
concurring to the increased susceptibility to develop autoimmunity in WAS patients.
Anna Villa
Gene transfer into stem cells Unit
Preclinical evaluation of safety and efficacy of gene therapy for
β-thalassemia: the first GLP toxicology study for an advanced therapy
-thalassemia is a severe congenital anemia
caused by deficiency of β-globin production. At
present, the only curative approach is represented by allogeneic hematopoietic stem cell transplantation (HSCT), which, however, is limited by
HLA compatibility and toxicity.
Gene therapy for β-thalassemia is based on the
autologous transplantation of hematopoietic stem
cells (HSPCs) engineered to express the human
β-globin gene and lentiviral vectors are the vectors of choice.
Starting from the demonstration of proof of efficacy in thalassemic mice and in hematopoietic cells
harvested by thalassemic patients, we moved towards the clinical development by assessing the
risk/benefit, in comprehensive in vivo pre-clinical
studies, testing toxicology and tumorigenicity of
genetically modified murine HSPCs and biodistribution of transduced human CD34+ progenitors
following transplantation in immunodeficient mice.
Evaluating the biosafety of gene therapy medicinal
products under regulatory compliance, utilizing
GLPs (good laboratory practices), provides results of scientific significance within regulatory
standards, and paves the way towards future
market registration. We developed a GLP Test Facility according to OECD Principles on GLP, combining the different expertise of personnel trained
in research, R&D, pathology and safety assessment, and quality assurance. Several laboratories
dedicated to GLP activities were appropriately
equipped, documentation required for quality
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
management, GLP procedures and analytical
methods were assembled and all personnel involved were specifically trained. Instruments were
qualified and most of the analytical procedures
were developed and validated according to EMA,
CBER/FDA and ICH guidelines.
In this context, we treated by gene therapy thalassemic mice, using cell dose and vector copy
number/cell superior to that expected in human
cells. Mice have been monitored for 12 months
and at termination full necropsy and histopathology
examination were performed along with clinical
chemistry, hematological evaluation and integration
site analysis. Overall, the final results show absence of increased tumorigenicity and genotoxicity associated to gene therapy and represent the
proof of safety and efficacy for the clinical trial.
Giuliana Ferrari
Hematopoietic stem cell based gene therapy for the
treatment of lysosomal storage disorders Unit
In most Lysosomal Storage Disorders (LSD)
hematopoietic stem cell (HSC) transplantation is
not or poorly effective. HSC gene therapy could
ameliorate the outcome of allogeneic transplant
and provide an expectation of efficacious treatment for these LSD. HSC can be genetically
modified to express supra-normal levels of the
therapeutic enzyme, and become a quantitatively
more effective source of functional enzyme than
normal donor’s cells. Moreover, autologous HSC
are immediately available, thus saving precious
time in rapidly progressing forms, and can significantly reduce transplant-related morbidity and
mortality. We are thus implementing an innovative
approach based on the transplantation of autologous, gene corrected HSC for the treatment of
severe LSD lacking efficacious and safe therapeutic opportunities. To this goal, we exploit the
features of lentiviral vectors (LV). By using LV for
HSC gene correction, we proved the therapeutic
potential of HSC gene therapy in the murine model of three different LSDs. In the case of
metachromatic leukodystrophy (MLD), a severe
dysmyelinating LSD, preclinical research led to
Phase I/II clinical testing. Indeed, a clinical trial of
HSC gene therapy for MLD is currently open to
patient’s recruitment and thus far 9 patients have
been enrolled and treated. Evidence of tolerability
and safety of the proposed approach, as well as
of therapeutic efficacy in the treated patients have
been obtained. The same approach has been
applied with success to the murine models of
type I Mucopolysaccharidosis (MPS I), a LSD
characterized by visceral organ, skeleton and
nervous system involvement, and of globoid
leukodystrophy (GLD), a demyelinating LSD similar to MLD. A clinical development plan for these
two diseases has been started with a Phase I/II trial of HSC gene therapy for MPSI patients planned
for late 2014-early 2015. We are also experimentally addressing the critical need of enhancing
brain microglia turnover with donor cells following
HCT in order to anticipate the time of clinical benefit and improve the efficacy of the transplant procedure. This work thus far provided hints for designing novel and less invasive approaches for
treating LSDs having a prevalent or exclusive
CNS involvement.
Alessandra Biffi
Immunological tolerance Unit
The goal of our Unit is to investigate the mechanisms that promote tolerance, and to identify novel therapies to prevent/cure immune-mediated
diseases. We focus on the role of T regulatory
cells (Tregs); specifically on Tr1 and FOXP3+
Tregs. The specific aims of our research are: 1) To
define Tr1 cell-gene signature; 2) To develop a
platform to generate Ag-specific Tr1 cells using
lentiviral vectors (LVs) encoding for human IL-10
(LV-hIL-10); 3) To test the efficacy of IL-10engineered T cells in humanized mouse models;
4) To investigate the mechanisms underlying tolerance induced by in vivo delivery of miRNA-regulated LVs; 5) To evaluate the efficacy of the miRNA-regulated LV platform for prevention or treatment of autoimmune diseases.
Achievements: 1) Defined the Tr1-specific gene
signature; 2) Demonstrated that enforced expression of hIL-10 by LVs confers a Tr1 phenotype
and function to human CD4+ (CD4IL-10) T cells;
3) Showed that CD4IL-10 cells suppress T-cell
responses in vitro and in vivo; 4) Induced Ag-spe123
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Research Units, HSR-TIGET
cific FOXP3+ Tregs in vivo by injection of LVs that
target Ag expression to hepatocytes by combining transcriptional (ET promoter), and post-transcriptional (miR142-target sequences (142T))
gene regulation; 5) Determined that Ag-specific
FOXP3+ Treg-induction is TGF-β-mediated; 6)
Demonstrated that a single injection of LV.ET.142T
encoding for Insulin-B9-23 prevents diabetes development in NOD mice.
Conclusions and future plans: 1) The identification
of Tr1-specific biomarkers is a major step forward
to understand the biology and to monitor these
cells in vivo. The Tr1-specific gene signature will
be investigated using different Tr1 cell sources
and functional studies will be performed to delineate the role of the identified genes; 2 and 3) The
ability to generate large numbers of human
CD4IL-10 cells with regulatory properties open
the possibility to use these cells for cellular therapy. The potential of LV-hIL-10 to convert Ag-specific effector T cells into Tr1 cells will be investigated; 4 and 5) The LV.ET.142T platform can be
used to prevent immune responses and induce
tolerance to transgenes in gene therapy or to selfAgs in autoimmune diseases. We will investigate
the efficacy of this platform in blocking ongoing
autoimmune diseases.
Maria Grazia Roncarolo
Genetic autoimmune diseases
Novel insights into the pathogenesis and diagnosis of immune
deficiencies with autoimmunity: towards innovative therapeutic strategies
In the past years, our studies on Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked
(IPEX) syndrome have significantly advanced the
understanding of the physiological role of FOXP3
in human regulatory T cells (Treg) and effector T
cells, and provided insights in the diagnosis and
pathogenesis of this devastating genetic autoimmune disease.
More recently, our research focused on defining
new therapeutic approaches for IPEX patients, as
alternative to hematopoietic stem cell (HSC)
transplantation, which is not always feasible. We
showed that, upon lentivirus-mediated FOXP3
gene transfer CD4+ T cells are converted into
Treg. The resulting CD4FOXP3 T cell population
displays stable phenotype and suppressive function, especially when naïve T cells are converted.
CD4FOXP3 T cells are stable in inflammatory
conditions not only in vitro, but also in vivo in a
model of xenogeneic graft-versus-host-disease.
IPEX-derived CD4FOXP3 T cells mirrored Treg
cells from healthy donors in terms of cellular markers, anergic phenotype, cytokine production, and
suppressive function. These findings suggest the
feasibility of adoptive cell therapy with genetically
engineered Treg cells for the treatment of IPEX
patients. With the ultimate goal of replacing the
mutated gene into autologous HSC, we are currently studying the effect of FOXP3 overexpression or knock-down in HSC in vitro and in vivo in
humanized-mice. This will allow us to track
FOXP3 in shaping human (effector and regulatory)
T cell development and better define the best
gene transfer strategy to be adopted to restore
immune tolerance and cure the disease. To get a
complete picture, we are also assessing the contribution of epigenetic regulators in controlling human T cell development.
In parallel, we are extending our studies to a wider
cohort of patients with early onset genetic autoimmunity, with or without enteropathy, and several of
them also affected by B cell dysfunction. We are
applying a system biology approach, combining
genomic analysis with immuno-functional studies
to identify the causative genes and altered pathways in these diseases. Altogether, results from
these research projects will be instrumental for
the definition of new targeted therapeutic intervention to re-establish immune tolerance.
Rosa Bacchetta
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Pathogenesis and therapy of ADA-SCID Unit
Genetic defects in adenosine deaminase (ADA)
lead to severe combined immunodeficiency
(SCID). Our studies investigate the immune alterations and onset of autoimmunity in ADA-SCID.
We also study vector integrations (IS) in patients
treated with hematopoietic stem cell (HSC) gene
therapy (GT) to understand the dynamics of genetically modified cells. In addition, we develop
new therapeutic strategies using lentiviral vectors
for ADA-SCID and other immunodeficiencies.
Since B-cell tolerance defects contribute to autoimmunity in this disease, we compared the efficacy of various treatments on B-cell development
and function. HSC-GT with a retroviral vector carrying the ADA cDNA reverted the block in bone
marrow development and progressively increased
B-cell numbers. Gene-corrected B cells displayed a strong selective advantage after egress
into the periphery (Figure 20A-B), leading to restored B-cell proliferative responses and antibody
secretion. Levels of correction correlated with the
percentage of vector-positive cells (Figure 20C),
indicating an advantage for endogenous ADA expression in B cells to recover B-cell development
and function. Increased gene transfer efficiency
through a lentivirus-based platform might further
accelerate B-cell reconstitution and reduce the
risk of autoimmunity.
To evaluate the long-term activity of transplanted
HSC we exploited data derived from the IS-based
tracking of 4.845 clones in ADA-SCID patients.
Identical IS were consistently detected at multiple
lineages level for up to 6 years after GT. By semiquantitative PCR on specific vector-genome junctions we tracked a fluctuating but consistent output of marked HSC without phases of clonal quiescence. Since a gammaretroviral vector was
used in this trial, which is able to transduce only
actively replicating cells, we provided the first evidence that in vitro activated HSC, “awaken” from
dormancy may retain in vivo long-term activity in
humans. We are exploiting IS similarities among
the lineages from ADA-SCID and other datasets
to reconstruct the hematopoietic hierarchy. Preliminary data unveiled a link between myeloid progenitors and mature lymphoid cells that supports
the recently suggested model of delayed branching of these lineages during hematopoiesis.
Alessandro Aiuti
Figure 20.
Selective
advantage and
functionality of
gene-corrected B
cells in patients
with ADA-SCID.
Adapted from:
Brigida, I et al.,
J. Allergy Clin.
Immunol.: 2014;
133(3): 799806.e10 doi:
10.1016/j.jaci.201
3.12.1043
125
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Research Units, HSR-TIGET
Safety of gene therapy and insertional mutagenesis Unit
We developed and validated novel highly sensitive tumor prone mouse models able to test the
genotoxicity of gene therapy vector integrations in
hematopoietic and liver tissues and to identifiy
novel genes involved in cancer (Ranzani M. et al.,
2013 Nature Methods, Nowrouzi A. et al., 2013
Molecular Therapy and Ranzani M. et al., 2013
Molecular Cancer Research). In this context we
also generated double knockout mice harboring
the null mutations for the Cdkn2a and WiskottAldrich syndrome (WAS) genes. The study of
these mice were instrumental also to address
WAS protein deficiency in natural killer and dendritic cells affects antitumor immunity (Catucci M
et al., 2013 European Journal of Immunology).
Moreover, we generated novel protocols and algorithms for integration site analysis for preclinical
testing and clinical trials. These advancements in
technologies and know-how have been instrumental to investigate the crosstalk between inte-
grated proviral and cellular host genome, study
basic mechanisms of insertional mutagenesis and
to test and validate, at the molecular level and in
vivo, novel LV designs with a superior safety profile
and that could be potentially adopted future clinical
trials. Finally, we successfully setup a centralized
core for standardized integration site retrieval and
analysis and performed the molecular monitoring
of the hematopoiesis in gene therapy patients from
our two recent clinical trials for the therapy of
metachromatic leukodystrophy and WAS. Our data
provided evidence that efficient ex vivo gene transfer occurred and was followed by substantial engraftment and sustained clonogenic activity of the
transduced hematopoietic stem cells in the patients, allowing polyclonal reconstitution of hematopoiesis with gene corrected cells to near homogeneity (Biffi A.*, Montini E.* et al., 2013 Science and
Aiuti A. Et al., 2013 Science).
Eugenio Montini
Tolerogenic dendritic cells Unit
The final goal of our group is to better characterize
the role of HLA-G-expressing DC-10, tolerogenic
DC that promote T regulatory type 1 (Tr1) cells, via
the IL-10-dependent HLA-G/ILT4 pathway, in dictating immune tolerance induction, and to identify
their clinical therapeutic application. Aims: 1) To
dissect the role of HLA-G in modulating tolerogenic properties of DC-10; 2) To define the correlation between HLA-G genetic and its expression
on DC-10 and to investigate the impact of miRNA
in post-transcriptional regulation of HLA-G in DC10; 3) To identify biomarkers for DC-10 selection
in vivo and the specific DC-10 gene signature; 4)
To outline new mechanisms of DC-10-mediated
immune-modulation; 5) To elucidate the localization and mode of action of DC-10 in vivo.
Achievements: 1) The expression of HLA-G on
DC-10 is donor-dependent, and high expression
of membrane-bound HLA-G is required for efficient IL-10-mediated induction of Tr1 cells via
DC-10. 2) Specific 3’UTR HLA-G genotypes are
associated with the expression of membranebound HLA-G on DC-10 and, consequently with
their tolerogenic properties. 3) The genomic and
miRNA profiles of DC-10 have been delineated.
4) DC-10 modulate not only CD4+ but also CD8+
T cell responses in vitro. 5) DC-10 are present at
high frequency in human decidua during the first
trimester of pregnancy and in peripheral blood of
AML patients.
Conclusions: The expression of membranebound HLA-G on DC-10 is genetically defined,
and is needed for reinforce DC-10-mediated generation of Tr1 cells. DC-10 are characterized by a
specific gene signature that put them as central
determinants of a tolerogenic path; future studies
will better delineate the multiple roles of DC-10 in
promoting tolerance. High frequency of DC-10 is
associated with tolerance in pregnancy. These
findings open new perspectives for DC-10 clinical
application: DC-10 are currently used to generate
allo-specific Tr1 cells for adoptive Treg-based cell
therapy, but they represent an interesting therapeutic tool to induce or re-establish immunological tolerance in different clinical settings including
allogeneic transplantation or autoimmune diseases.
Silvia Gregori
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Clinical Research Units, HSR-TIGET
PCRU - Gene therapy for Wiskott-Aldrich Syndrome
Wiskott-Aldrich Syndrome (WAS) is an X-linked
immunodeficiency characterized by thrombocytopenia, infections, and an increase risk to develop autoimmunity and lymphomas. Despite
progress in allogeneic transplantation of
hematopoietic stem/progenitor cells (HSC), the
use of mismatched donors is still associated with
substantial complications. Gene therapy with ex
vivo transduced HSC could represent a valid therapeutic option for patients lacking an HLA-identical donor. We developed an approach based on
a lentiviral vector (LV) encoding for WAS under the
control of the homologous 1.6 kb WAS promoter
(Aiuti et al., Science 2013). A phase I/II clinical trial
based on infusion of autologous transduced HSC
cells and reduced intensity conditioning started in
June 2010. Six patients were treated with autologous bone marrow (BM) or mobilized peripheral
blood (PB) derived CD34+ cells transduced with
highly purified LV. Results relating to the first four
patients followed for up to 3.5 years, showed that
transduction of clonogenic progenitors in vitro
was highly efficient (>90%). This led to robust and
stable engraftment observed in BM (including
clonogenic progenitors), PB myeloid cells and
lymphocytes. Accordingly, WASP expression,
measured by flow-cytometry, was observed in
monocytes and, as expected due to the selective
advantage, in a higher percentage of B and T
cells cells. TCR driven proliferation was improved
also at low doses of anti-CD3 monoclonal antibody, which are typically defective in WAS. TCR
repertoire and immunological functions, including
NK cytotoxic ability, and Treg function, were also
improved after GT. WASP expression was also restored in the majority of platelets, leading to an increase in their number. All patients are currently
clinically well, independent from platelet transfusions. Insertions analyses confirm that
hematopoiesis remains highly polyclonal, in the
absence of aberrant clonal expansion. In conclusion, the high level of gene transfer obtained with
LV-WAS results in stable engraftment of transduced HSC and restored WAS expression even
when combined to reduced intensity conditioning.
Although a longer observation is required to establish the long-term safety, lentiviral gene therapy
represents a promising treatment for WAS.
Maria Grazia Roncarolo and Alessandro Aiuti
PCRU - ADA gene transfer into hematopoietic stem cells
for the treatment of ADA-SCID
SCID due to adenosine deaminase deficiency
(ADA-SCID) is characterized by impaired lymphoid development and function, and systemic
manifestation of metabolic toxicity. Since year
2000, we have treated 18 children with autologous CD34+ cells transduced with a gammaretroviral encoding ADA combined to reduced
intensity conditioning with busulfan. Median age
at treatment was 1.7 years (range: 0.5 to 6.1);
83% of patients had received enzyme replacement therapy (ERT) before gene therapy. As of
December 31st, 2013, all patients are alive and
well, with a median follow up of 7.2 years. Three
subjects required reintroduction of ERT or allogeneic bone marrow (BM) transplantation while
15 patients remain off ERT. ADA transduced cells
continue to be stably detected by PCR in multiple
lineages of the BM and peripheral blood, leading
to an effective reduction of systemic dAXP. T cell
counts, including CD4+ naïve T cells, and in vitro
T-cell proliferative responses have improved significantly after gene therapy. IVIg infusions have
been discontinued in 12 patients, with positive response to vaccinations. Severe infections have
progressively decreased after gene therapy. No
event of insertional oncogenesis has been detected during the follow up, in agreement with the
polyclonal pattern of vector integration by insertion
site analyses. Study on patients receiving infusions of transduced lymphocytes or CD34+ cells
allowed tracking of single T-cell clones and investigating the survival potential and hierarchical relationships of naive and memory subpopulations directly in vivo. In summary, these data confirm the
favourable risk-benefit profile of gene therapy for
ADA-SCID and support further development of
this therapy.
Alessandro Aiuti and Maria Grazia Roncarolo
127
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Clinical Research Units, HSR-TIGET
PCRU - Clinical trial of gene therapy in metachromatic
leukodystrophy
Phase I/II clinical trial of hematopoietic stem cell gene therapy for the
treatment of Metachromatic Leukodystrophy
Metachromatic Leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder
caused by Arylsulfatase A (ARSA) deficiency and
leading to severe demyelination, neurodegeneration and premature death of the affected patients.
Currently, no treatment can halt the progression of
this devastating disease. According to relevant
preclinical data, and based on the experience we
acquired on the natural clinical course of the disease, on March 2010 a clinical trial based on
transplantation of autologous hematopoietic stem
cells transduced with LVs encoding ARSA was
approved by the Italian Regulatory Authorities. The
clinical protocol foresees the enrollment of 8 late
infantile (LI) and 2 early juvenile (EJ) patients, in
pre- and, in the case of EJ patients, early-symptomatic stage, in order to provide them a reasonable expectation of clinical benefit. The study objectives are the evaluation of the safety of the
treatment, related to the myeloablative conditioning regimen employed and to the use of LVs, and
of its efficacy by measuring patients’ motor abilities and demyelination occurring in the nervous
system through the use of validated instrumental
readouts. By end of 2013 nine patients have
been enrolled and treated. Thus far, we can report
a favorable outcome of the transplant procedure
with a good bone marrow recovery and the
short/medium-term safety of both the conditioning regimen and stem cell transduction with LVs.
Moreover, we report stable sustained ARSA gene
replacement in the reconstituted hematopoiesis
of the patients, and ARSA activity reconstitution in
the cerebrospinal fluid, the latter thus far documented in the first three treated patients. These
findings are associated with evidence of therapeutic benefit. These data are extremely encouraging, even if only the long-term follow-up of all
the treated patients will confirm this favorable indication.
Maria Sessa and Alessandra Biffi
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Selected publications
Aiuti, A; Biasco, L and Scaramuzza, S; Ferrua, F; Cicalese, MP; Baricordi, C; Dionisio, F; Calabria, A; Giannelli, S; Castiello, MC; Bosticardo, M; Evangelio, C; Assanelli, A; Casiraghi, M;
Di Nunzio, S; Callegaro, L; Benati, C; Rizzardi, P; Pellin, D, Di Serio, C; Schmidt, M; Von Kalle, C;
Gardner, J; Mehta, N; Neduva, V; Dow, DJ; Galy, A; Miniero, R; Finocchi, A; Metin, A; Banerjee, P;
Orange, J; Galimberti, S; Valsecchi, MG; Biffi, A; Montini, E; Villa, A; Ciceri, F; Roncarolo, MG
and Naldini, L. Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich
Syndrome. Science: 2013; 341(6148): 123351 - Article
IF 2012: 31,027
Biffi, A and Montini, E; Lorioli, L; Cesani, M; Fumagalli, F; Plati, T; Baldoli, C; Martino, S; Calabria, A; Canale, S; Benedicenti, F; Vallanti, G; Biasco, L; Leo, S; Kabbara, N; Zanetti, G; Rizzo,
WB; Mehta, NA; Cicalese, MP; Casiraghi, M; Boelens, JJ; Del Carro, U; Dow, DJ; Schmidt, M;
Assanelli, A; Neduva, V; Di Serio, C; Stupka, E; Gardner, J; von Kalle, C; Bordignon, C; Ciceri,
F; Rovelli, A; Roncarolo, MG; Aiuti, A; Sessa, M; Naldini, L. Lentiviral Hematopoietic Stem Cell
Gene Therapy Benefits Metachromatic Leukodystrophy. Science: 2013; 341(6148): 1233158 - Article
IF 2012: 31,027
Casucci, M; Perna, SK; Falcone, L; Camisa, B; Magnani, Z; Bernardi, M; Crotta, A; Tresoldi,
C; Fleischhauer, K; Ponzoni, M; Gregori, S; Caligaris-Cappio, F; Ciceri, F; Bordignon, C;
Cignetti, A; Bondanza, A and Bonini, C. Graft-versus-leukemia effect of HLA-haploidentical central-memory t-cells expanded with leukemic APCs and modified with a suicide gene. Mol. Ther.:
2013; 21(2): 466-475 - Article
IF 2012: 7,041
Casucci, M; Nicolis di Robilant, B; Falcone, L; Camisa, B; Norelli, M; Genovese, P; Gentner,
B; Gullotta, F; Ponzoni, M; Bernardi, M; Marcatti, M; Saudemont, A; Bordignon, C; Savoldo, B;
Ciceri, F; Naldini, L; Dotti, G; Bonini, C; Bondanza, A. CD44v6-targeted T cells mediate potent
antitumor effects against acute myeloid leukemia and multiple myeloma. Blood: 2013; 122(20):
3461-3472 - Article
IF 2012: 9,060
Patel, AS; Smith, A; Nucera, S; Biziato, D; Saha, P; Attia, RQ; Humphries, J; Mattock, K; Grover,
SP; Lyons, OT; Guidotti, LG; Siow, R; Ivetic, A; Egginton, S; Waltham, M; Naldini, L; De Palma, M
and Modarai, B. TIE2-expressing monocytes/macrophages regulate revascularization of the ischemic limb. EMBO Mol. Med.: 2013; 5(6): 858-869 - Article
IF 2012: 7,795
Gagliani, N and Magnani, CF and Huber, S; Gianolini, ME; Pala, M; Licona-Limon, P; Guo, B;
Herbert, DR; Bulfone, A; Trentini, F; Di Serio, C; Bacchetta, R; Andreani, M; Brockmann, L; Gregori, S and Flavell, RA and Roncarolo, MG. Coexpression of CD49b and LAG-3 identifies human
and mouse T regulatory type 1 cells. Nat. Med.: 2013; 19(6): 739-746 - Article
IF 2012: 24,302
Passerini, L; Rossi Mel, E; Sartirana, C; Fousteri, G; Bondanza, A; Naldini, L; Roncarolo, MG;
Bacchetta, R. CD4+ T Cells from IPEX Patients Convert into Functional and Stable Regulatory T
Cells by FOXP3 Gene Transfer. Sci. Transl. Med.: 2013; 5(215): 215ra174 - Article
IF 2012: 10,757
Ranzani, M; Cesana, D and Bartholomae, CC; Sanvito, F; Pala, M; Benedicenti, F; Gallina, P;
Sergi Sergi, L; Merella, S; Bulfone, A; Doglioni, C; Von Kalle, C; Kim, YJ; Schmidt, M; Tonon, G;
Naldini, L; Montini, E. Lentiviral vector-based insertional mutagenesis identifies genes associated
with liver cancer. Nat. Methods: 2013; 10(2): 155-161 - Article
IF 2012: 23,565
Zonari, E; Pucci, F; Saini, M; Mazzieri, R; Politi, LS; Gentner, B; Naldini, L. A role for miR-155 in
enabling tumor-infiltrating innate immune cells to mount effective antitumor responses in mice.
Blood: 2013; 122(2): 243-252 - Article
IF 2012: 9,060
Cieri, N; Camisa, B; Cocchiarella, F; Forcato, M; Oliveira, G; Provasi, E; Bondanza, A; Bordignon, C; Peccatori, J; Ciceri, F; Lupo-Stanghellini, MT; Mavilio, F; Mondino, A; Bicciato, S;
Recchia, A; Bonini, C. IL-7 and IL-15 instruct the generation of human memory stem T cells from
naive precursors. Blood: 2013; 121(4): 573-584 - Article
129
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Selected publications, HSR-TIGET
IF 2012: 9,060
Sundarasetty, BS; Singh, VK; Salguero, G; Geffers, R; Rickmann, M; Macke, L; Borchers, S;
Figueiredo, C; Schambach, A; Gullberg, U; Provasi, E; Bonini, C; Ganser, A; Woelfel, T; Stripecke,
R. Lentivirus-induced dendritic cells for immunization against high-risk WT1+ acute myeloid
leukemia. Hum. Gene Ther.: 2013; 24(2): 220-237 - Article
IF 2012: 4,019
Rigamonti, E; Touvier, T; Clementi, E; Manfredi, AA; Brunelli, S and Rovere-Querini, P. Requirement of inducible nitric oxide synthase for skeletal muscle regeneration after acute damage. J. Immunol.: 2013; 190(4): 1767-1777 - Article
IF 2012: 5,520
Lo-Coco, F; Avvisati, G; Vignetti, M; Thiede, C; Orlando, SM; Iacobelli, S; Ferrara, F; Fazi, P; Cicconi, L; Di Bona, E; Specchia, G; Sica, S; Divona, M; Levis, A; Fiedler, W; Cerqui, E; Breccia, M;
Fioritoni, G; Salih, HR; Cazzola, M; Melillo, L; Carella, AM; Brandts, CH; Morra, E; Von Lilienfeld-Toal,
M; Hertenstein, B; Wattad, M; Lubbert, M; Hanel, M; Schmitz, N; Link, H; Kropp, MG; Rambaldi, A;
La Nasa, G; Luppi, M; Ciceri, F; Finizio, O; Venditti, A; Fabbiano, F; Dohner, K; Sauer, M; Ganser, A;
Amadori, S; Mandelli, F; Dohner, H; Ehninger, G; Schlenk, RF; Platzbecker, U; for Gruppo Italiano
Malattie Ematologiche dell’ Adulto; the German-Austrian Acute Myeloid Leukemia Study Group; and
Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. New
Engl. J. Med.: 2013; 369(2): 111-121 - Article
IF 2012: 51,658
Todisco, E; Ciceri, F; Oldani, E; Boschini, C; Mico, C; Vanlint, MT; Donnini, I; Patriarca, F; Alessandrino, PE; Bonifazi, F; Arcese, W; Barberi, W; Marenco, P; Terruzzi, E; Cortelazzo, S; Santarone, S;
Proia, A; Corradini, P; Tagliaferri, E; Falcioni, S; Irrera, G; Dallanegra, L; Castagna, L; Santoro, A;
Camboni, A; Sacchi, N; Bosi, A; Bacigalupo, A; Rambaldi, A. The CIBMTR score predicts survival of
AML patients undergoing allogeneic transplantation with active disease after a myeloablative or reduced intensity conditioning: A retrospective analysis of the Gruppo Italiano Trapianto di Midollo Osseo. Leukemia: 2013; 27(10): 2086-2091 - Letter
IF 2012: 10,164
Neguembor, MV; Xynos, A; Onorati, MC; Caccia, R; Bortolanza, S; Godio, C; Pistoni, M; Corona, DF; Schotta, G; Gabellini, D. FSHD muscular dystrophy region gene 1 binds Suv4-20h1 histone methyltransferase and impairs myogenesis. J.Mol. Cell Bio.: 2013; 5(5): 294-307 - Article
IF 2012: 7,308
Selected publications, HSR-TIGET
(see also the list under Division of Regenerative Medicine, Stem Cell and Gene Therapy)
Amendola, M; Giustacchini, A; Gentner, B; Naldini, L. A double-switch vector system positively
regulates transgene expression by endogenous microRNA expression (miR-ON vector). Mol. Ther.:
2013; 21(5): 934-946 - Article
IF 2012: 7,041
Annoni, A and Cantore, A; Della Valle, P; Goudy, K; Akbarpour, M; Russo, F; Bartolaccini, S;
D’Angelo, A; Roncarolo, MG and Naldini, L. Liver gene therapy by lentiviral vectors reverses antifactor IX pre-existing immunity in haemophilic mice. EMBO Mol. Med.: 2013; 5(11): 1684-1697 - Article
IF 2012: 7,795
Lattanzi, A and Gentner, B; Corno, D; Di Tomaso, T; Mestdagh, P; Speleman, F; Naldini, L;
Gritti, A. Dynamic Activity of miR-125b and miR-93 during Murine Neural Stem Cell Differentiation In
Vitro and in the Subventricular Zone Neurogenic Niche. PloS One: 2013; 8(6): e67411 - Article
IF 2012: 3,730
McMurchy, AN; Gillies, J; Gizzi, MC; Riba, M; Garcia-Manteiga, JM; Cittaro, D; Lazarevic, D; Di
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Nunzio, S; Piras, IS; Bulfone, A; Roncarolo, MG; Stupka, E; Bacchetta, R and Levings, MK. A
novel function for FOXP3 in humans: intrinsic regulation of conventional T cells. Blood: 2013; 121(8):
1265-1275 - Article
IF 2012: 9,060
Scaramuzza, S and Biasco, L; Ripamonti, A; Castiello, MC; Loperfido, M; Draghici, E; Hernandez, RJ; Benedicenti, F; Radrizzani, M; Salomoni, M; Ranzani, M; Bartholomae, CC; Vicenzi,
E; Finocchi, A; Bredius, R; Bosticardo, M; Schmidt, M; von Kalle, C; Montini, E; Biffi, A; Roncarolo, MG; Naldini, L; Villa, A; Aiuti, A. Preclinical Safety and Efficacy of Human CD34(+) Cells
Transduced With Lentiviral Vector for the Treatment of Wiskott-Aldrich Syndrome. Mol. Ther.: 2013;
21(1): 175-184 - Article
IF 2012: 7,041
131
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Functional genetics of muscle regeneration
Neural stem cell biology
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Autoimmunity & vascular inflammation Unit
Gene expression and muscular dystrophy Unit
133
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Research Units
Molecular and functional immunogenetics Unit
Hematology and hematopoietic stem cell transplantation Unit
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Gene therapy for WASP/Omenn Unit
Hematopoietic stem cell based gene therapy for the treatment of lysosomal storage disorders Unit
135
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Research Units
Pathogenesis and therapy of ADA-SCID Unit
Tolerogenic dendritic cells Unit
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Safety of gene therapy and insertional mutagenesis Unit
137
DIVISION
OF
Immunology, Transplantation,
and Infectious Diseases
Director:
Luca G. Guidotti,
since June 2013
Director:
Ruggero Pardi*,
until May 2013
Associate Director:
Adriano Lazzarin*
Research Units
Immunopathology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 147
HEAD OF UNIT: Luca G. Guidotti, ERC Advanced Grant
RESEARCHER: Giovanni Sitia
POST-DOCTORAL FELLOW: Mario Catarinella
PHD STUDENT: Roberto Aiolfi**
FELLOW: Andrea Monestiroli
TECHNICIANS: Tiziana Cataudella, Diego Covarello, Pietro Di Lucia, Amleto Fiocchi, Bruno
Fiore, Marta Mainetti, Michele Raso
Cellular and molecular allergology ––––––––––––––––––––––––––––––––––––––––––––––– 147
GROUP LEADER: Samuele E. Burastero
TECHNICIANS: Daniela Breda, Marco Rossi
Human virology –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 148
GROUP LEADER: Mauro S. Malnati
FELLOW: Davide De Battista
TECHNICIAN: Francesca Sironi
Protein engineering and therapeutics –––––––––––––––––––––––––––––––––––––––––––– 148
GROUP LEADER: Luca Vangelista
POST-DOCTORAL FELLOW: Massimiliano Secchi
γδ T cells in innate and adaptive immunity ––––––––––––––––––––––––––––––––––––– 149
RESEARCHER: Maria Raffaella Zocchi
FELLOWS: Caterina Camodeca, Paolo Canevali, Silvia Catellani
139
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Research Units
Infectious diseases Unit
HEAD OF UNIT: Adriano Lazzarin*
Immunobiology of HIV ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 150
GROUP LEADER: Lucia Lopalco
POST-DOCTORAL FELLOW: Assunta Venuti
FELLOW: Riccardo Miglietta
TECHNICIAN: Claudia Pastori
AIDS immunopathogenesis Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 150
HEAD OF UNIT: Guido Poli*
RESEARCHER: Massimo Alfano
POST-DOCTORAL FELLOW: Elisa Saba
PHD STUDENTS: Marylinda Famiglietti**, Luca Genovese**, Francesca Graziano**
Biocrystallography Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 150
HEAD OF UNIT: Massimo Degano
POST-DOCTORAL FELLOWS: Giovanna Avella, Claudia Minici, Marco Patrone
TECHNICIAN: Paola Tornaghi
Cellular immunology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 152
HEAD OF UNIT: Matteo Bellone
POST-DOCTORAL FELLOW: Elena Jachetti
PHD STUDENTS: Arianna Calcinotto**, Alessia Ricupito**
TECHNICIAN: Matteo Grioni
Dynamics of immune responses Unit ––––––––––––––––––––––––––––––––––––––––––––––––––– 152
GROUP LEADER: Matteo Iannacone, Armenise-Harvard Career Development Award and ERC
starting grant
POST-DOCTORAL FELLOWS: Jessica Fioravanti, Nereida Jiménez de Oya, Mirela Kuka,
Stefano Sammicheli, Laura Sironi
PHD STUDENTS: Marco De Giovanni**, Donato Inverso**
FELLOWS: Silvia Burati**, Lorenzo Fossati**, Lucia Ganzer
Emerging bacterial pathogens Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––– 153
HEAD OF UNIT: Daniela Maria Cirillo
POST-DOCTORAL FELLOWS: Emanuele Borroni, Lucinda Furci, Paolo Miotto, Elisa Tagliani,
Enrico Tortoli
PHD STUDENTS: Andrea Cabibbe, Elisa Schena
FELLOWS: Riccardo Alagna, Alberto Trovato, IIaria Valente
TECHNICIAN: Rossella Baldan, Paola Mantegani
Experimental immunology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 154
HEAD OF UNIT: Paolo Dellabona
RESEARCHERS: Giulia Casorati, Claudia De Lalla
PHD STUDENTS: Michela Consonni**, Filippo Cortesi**, Francesca Gorini**
FELLOWS: Maya Fedeli, Daniele Mennonna
TECHNICIAN: Claudio Garavaglia
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Research Units
Infection and cystic fibrosis Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 154
GROUP LEADER: Alessandra Bragonzi
POST-DOCTORAL FELLOWS: Irene Bianconi, Cristina Cigana**, Ida De Fino, Marcella
Facchini (until April 2013), Nicola Ivan Lorè
PHD STUDENTS: Beatriz Alcalà-Franco, Maura De Simone, Lorenza Spagnuolo
FELLOWS: Camilla Riva, Alice Rossi
Leukocyte biology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 155
HEAD OF UNIT: Ruggero Pardi*
RESEARCHER: Monica Fabbri
POST-DOCTORAL FELLOWS: Carolina Lage Crespo, Raffaella Molteni, Michela Palmisano,
Martina Panattoni
FELLOW: Marcello Delfini
TECHNICIAN: Barbara Clissi
Lymphocyte activation Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 156
HEAD OF UNIT: Anna Mondino
POST-DOCTORAL FELLOW: Karolina Pilipow
PHD STUDENT: Tabea Sturmheit**
FELLOW: Valentina Guida
TECHNICIAN: Veronica Basso
Tumor immunology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 156
HEAD OF UNIT: Maria Pia Protti
RESEARCHER: Lucia De Monte
POST-DOCTORAL FELLOW: Giulia Di Lullo
PHD STUDENT: Emanuela Brunetto
TECHNICIAN: Silvia Heltai
Viral evolution and transmission Unit ––––––––––––––––––––––––––––––––––––––––––––––––––– 157
HEAD OF UNIT: Gabriella Scarlatti
POST-DOCTORAL FELLOWS: Mariangela Cavarelli, Stefania Dispinseri
TECHNICIAN: Monica Tolazzi
Viral pathogens and biosafety Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––– 158
HEAD OF UNIT: Elisa Vicenzi
PHD STUDENTS: Andrea Di Pietro**, Filippo Turrini**
TECHNICIANS: Silvia Ghezzi, Lucia Nicora
141
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Clinical Research Units
Infectious diseases Unit
HEAD OF UNIT: Adriano Lazzarin*
Management and antiretroviral treatment of HIV infection –––––––––––––––––– 159
CLINICAL GROUP LEADER: Antonella Castagna
PHYSICIAN: Nicola Gianotti
FELLOW: Vincenzo Spagnuolo**
RESEARCH NURSES: Alba Bigoloni, Concetta Vinci
STUDY COORDINATOR: Elisabetta Carini
DATA MANAGER: Stefania Salpietro
STATISTICIAN: Laura Galli
TECHNICIAN: Andrea Galli
BIOMEDICAL ENGINEER: Andrea Poli**
Neurovirology –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 159
CLINICAL GROUP LEADER: Paola Cinque
FELLOWS: Francesca Ferretti**, Valeria Longo
STUDY COORDINATORS: Maria Rita Parisi, Ester Tuveri
Study and treatment of hepatotropic viruses related diseases ––––––––––––– 160
CLINICAL GROUP LEADER: Caterina Uberti-Foppa
RESEARCHER: Giulia Morsica
POST-DOCTORAL FELLOWS: Sabrina Bagaglio, Hamid Ibrahim Hasson
FELLOWS: Marco Merli, Emanuela Messina
Vaccine and immunotherapy ––––––––––––––––––––––––––––––––––––––––––––––––––––––– 161
CLINICAL GROUP LEADER: Giuseppe Tambussi
PHYSICIAN: Silvia Nozza
FELLOWS: Stefania Chiappetta**, Manuela Pogliaghi**, Marco Ripa**
RESEARCH NURSE: Liviana Della Torre
TRIAL COORDINATOR: Maria Rita Parisi
TECHNICIAN: Andrea Galli
Clinical immunopathology and advanced medical therapeutics Unit ––––––––––––– 161
HEAD OF UNIT: Maria Grazia Sabbadini*
PHYSICIANS: Enrica P. Bozzolo, Giselda Colombo, Lorenzo Dagna*, Massimo Memoli, Luisa
Praderio, Moreno Tresoldi
POST-DOCTORAL FELLOWS: Patrizia Aiello, Emmanuel Della Torre**, Stefano Franchini, Mirta
Tiraboschi, Mona Rita Yacoub
FELLOWS: Alvise Berti, Corrado Campochiaro, Valentina Canti, Andrea Duca, Luca Ferrante,
Andrea Segalini, Cristina Sorlini, Enrico Tombetti
CONSULTANT: Elena Baldissera
Clinical transplant Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 162
HEAD OF UNIT: Antonio Secchi*
PHYSICIANS: Rossana Caldara, Chiara Gremizzi, Ennio La Rocca, Vera Paloschi
POST-DOCTORAL FELLOWS: Francesca D’Addio, Silvia Foti
CONSULTANT: Paolo Fiorina
RESEARCH NURSE: Barbara Pontiroli
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Clinical Research Units
Pancreatic tumors Unit: immunotherapy and β cell function substitution –––––– 162
HEAD OF UNIT: Marco Braga*
PHYSICIAN: Renato Castoldi
RESIDENT: Nicolò Pecorelli
Gynecological cancers immunology ––––––––––––––––––––––––––––––––––––––––––––––––––––– 163
HEAD OF UNIT: Massimo Candiani*
CLINICAL GROUP LEADER: Massimo Origoni*
PHYSICIAN: Luigi Caputo
RESIDENTS: Guia Carminati**, Chiara Stefani**
Immunology in liver neoplasms ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 163
HEAD OF UNIT: Gianfranco Ferla*
CLINICAL GROUP LEADER: Luca Aldrighetti
PHYSICIANS: Marco Catena, Renato Finazzi
RESIDENTS: Federica Cipriani **, Francesca Ratti**
Obesity and bariatric surgery –––––––––––––––––––––––––––––––––––––––––––––––––––––– 164
RESEARCHER: Michele Paganelli
Gastroenterology Unit
HEAD OF UNIT: Pier Alberto Testoni*
Clinical hepato-gastroenterology ––––––––––––––––––––––––––––––––––––––––––––––––– 164
RESEARCHER: Mario Guslandi
Digestive pathophysiology –––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 165
RESEARCHER: Sandro Passaretti
143
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
DRI
Diabetes Research Institute
Director:
Emanuele Bosi*
Associate Directors:
Manuela Battaglia,
Lorenzo Piemonti
Research Units
Diabetes research Unit
HEAD OF UNIT: Emanuele Bosi*
Experimental diabetes ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 167
GROUP LEADER: Marika Falcone
PHD STUDENTS: Caterina Di Pietro**, Chiara Sorini**
FELLOWS: Jayashree Dolpady, Alessandra Mandelli
TECHNICIAN: Alessandra Caputo
β cell biology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 167
HEAD OF UNIT: Lorenzo Piemonti
RESEARCHER: Rita Nano
POST-DOCTORAL FELLOWS: Paolo Monti, Valeria Sordi
PHD STUDENTS: Elisa Cantarelli**, Antonio Citro, Erica Dugnani, Simona Marzorati, Silvia
Pellegrini
FELLOWS: Daniela Liberati, Alessia Mercalli, Valentina Pasquale, Debora Vignali
TECHNICIAN: Raffaella Melzi
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Research Units/Clinical Research Units, DRI
Immune-mediated diseases Unit: from pathogenesis to treatment ––––––––––––––– 168
HEAD OF UNIT: Manuela Battaglia
POST-DOCTORAL FELLOW: Georgia Fousteri
PHD STUDENTS: Gian Maria Giamporcaro, Bechara Mfarrej, Celia Peral de Castro**, Andrea
Valle**
FELLOWS: Roberta Di Fonte, Antonio Martelli, Cristina Morsiani
TECHNICIANS: Tatiana Jofra, Angela Stabilini
Clinical Research Units
Prevention in Type 1 diabetes Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––– 169
HEAD OF UNIT: Emanuele Bosi*
PHYSICIANS: Sabina Martinenghi, Matteo Rocco Pastore
RESIDENT: Andrea Laurenzi
TRIAL COORDINATOR: Pauline Grogan
RESEARCH NURSE: Eleonora Bianconi
Epidemiology & data management ––––––––––––––––––––––––––––––––––––––––––––––– 169
RESEARCHER: Marina Scavini
Islet transplantation –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 169
HEAD OF UNIT: Antonio Secchi*
CLINICAL GROUP LEADER: Paola Maffi
DATA MANAGER: Paola Magistretti
RESEARCH NURSE: Luisa Zamberletti
Childhood diabetes –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 170
HEAD OF UNIT: Giuseppe Chiumello*
CLINICAL GROUP LEADER: Riccardo Bonfanti
RESIDENTS: Roseila Battaglino, Clara Bonura, Valeria Favalli, Giulio Frontino
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
145
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Introduction by the Directors
The Division of Immunology, Transplantation and Infectious Diseases (DITID) stems from a deeply integrated area of Institutional research at the San Raffaele Scientific Institute, dating back to the inception
of DIBIT and making up the scientific core of areas of intense clinical investigation, which include, but are
not limited to, cancer, type 1 diabetes, allergy, cell and solid organ transplantation and infectious diseases such as those caused by HIV, HBV and HCV.
Based on these premises, the unifying mission of the DITID is to harness the immune response for the
benefit of patients. To this aim, DITID fosters research efforts and development of new technologies aimed
at dissecting the mechanisms underlying the immune response to infectious agents, cancer- and transplantation-associated antigens, as well as the deregulation of processes controlling immunological tolerance. Basic discoveries are validated through a large variety of dedicated animal models and human
immune cells/tissues, with the goal of translating them into proof-of-concept clinical trials.
Over the last few years, DITID has also structured selected research activities into a limited set of Research
Programs, aimed at fostering interdisciplinary research and strong integration of pre-clinical and clinical
investigations. The Islet Transplantation Program (ITP) aims at achieving long-lasting insulin independence
in patients with type 1 diabetes (T1D) undergoing islet transplantation. The Program of Immunology and
Bio-immunotherapy of Cancer (PIBIC) seeks to provide a deeper understanding of the mechanisms underlying the tumor/immune system interaction and designs new immunotherapy strategies against different solid tumors. A third Program termed Correlates of HIV-Associated Immune Response Modulation
(CHARM) focuses on the role of the chemokine receptor CCR5 and its ligands in HIV infection and related clinical entities.
DITID personnel includes Faculty, Tenured Research Associates, Post-doctoral fellows, PhD Students,
Technicians, and Clinicians. Graduate training is currently provided within the frame of the Institutional
PhD Programs. PhD students are given the opportunity to participate to “ad hoc” courses mainly organized in the format of frontal Lectures by Invited Speakers followed by interactive Journal Club sessions.
Students are also offered the possibility to meet visiting scientists and to participate to national and international meetings. Post-graduate education is mainly provided by the possibility to attend and present
data to weekly-held DITID Meetings or Journal Clubs. Participation to the institutional San Raffaele Scientific Retreat (held once a year) is also strongly encouraged and particularly useful.
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Research Units
Immunopathology Unit
Pathogenesis of viral hepatitis and liver cancer
Hepatitis B virus (HBV) and hepatitis C virus (HCV)
are unique in their capacity to cause persistent infection, fibrosis/cirrhosis and hepatocellular carcinoma (HCC) in humans. The main objective of our
research is to define the cellular and molecular
mechanisms responsible for viral clearance and
disease pathogenesis during HBV or HCV infection. We expect that that results emerging for this
work will help the design of novel therapeutic approaches to prevent and cure these diseases.
The program takes advantage of infected patients, proprietary mouse models of viral hepatitis
and liver cancer, and new technological advances
in the field of live imaging (e.g. 7Tesla MRI and
single- or two-photon-based intravital microscopy). Using these resources, we have recently demonstrated that platelets play a central
role in the pathogenesis of viral hepatitis (i.e. they
facilitate the accumulation of pathogenic virusspecific T cells into the organ) and that daily lowdoses of anti-platelet drugs reduce the severity of
liver immunopathology and the development of fibrosis/cirrhosis and HCC in a mouse model of
immune-mediated chronic hepatitis. Additional
activities of our Unit include the implementation of
cell-based approaches attempting to cure established primary or secondary liver cancers. One
such approach involves the use of specialized
monocytes - termed Tie2 monocytes -, which accumulate preferentially in the proximity of tumors.
In collaboration with the Naldini’s lab, we reasoned to utilize Tie2 monocytes at the host advantage, i.e. to genetically manipulate them (so
that they produce anti-tumoral drugs such as IFNα) and use them as Trojan Horses delivering high
doses IFN-α only at tumor sites. Thus far, our preclinical efforts mainly involved mouse models of
colorectal cancer (CRC) liver metastases and
showed that mice reconstituted with bone marrow cells engineered to express IFN-α only in Tie2
monocytes display reduced tumor burden, increased signs of anti-tumoral immune activation
and overall improved survival. As these remarkable results are not associated to systemic signs
of toxicity, this work suggests that Tie2 monocytes expressing IFN-α might represent a new
and valuable cell therapy platform for the treatment of CRC liver metastases in humans.
Luca G. Guidotti
Cellular and molecular allergology
In the last decade, single allergen components
have been progressively substituting allergen extracts in allergy diagnosis and treatment. We previously characterized structural aspects of “allergoids”, i.e., allergens mutated in order to loose allergenicity while fully maintaining T-cell stimulatory
potential, to be used as candidates for immunotherapy in allergic diseases. Presently, we
are exploring (in collaboration with the Protein Biochemistry Unit) the presence of IgE to allergen
components which, although infrequently found in
the allergic population based on presently available allergen micro-array based diagnosis, represent sensitizations with a clinical impact in single
patients.
In parallel, we are investigating the role of diamine
oxidase (DAO), the main enzyme for the metabolism of histamine ingested with foods and/or released following IgE dependent reactions, in histamine intolerance. Histamine intolerance is a disputed clinical syndrome potentially capable to jus-
tify up to 34% of the requests of the patients referred to the Allergy Clinic. The altered balance
between histamine production and catabolism
can follow ingestion of histamine-rich food, drugs
releasing histamine and drugs blocking diaminoxidase. Several pathogenic steps follow, including
smooth muscle contraction, vasodilatation, extravasation of plasma from capillaries, and stimulation of gastric acid secretion. Together, these
mechanisms are responsible for such heterogeneous symptoms as diarrhea, epigastralgia, meteorism, headache, hypotension, arrhythmias, urticaria, pruritus, flushing, rhinitis and asthma. Association of functional polymorphisms in the
genes coding for DAO and histamine intolerance
will be also investigated. Evaluation of these clinical parameters in association with serum diamine
oxidase levels and expression of DAO polymorphisms will help to shed light on the pathogenesis
of histamine intolerance.
Samuele E. Burastero
147
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Research Units
Human virology
The failure of anti HIV-1 vaccine strategy based on
the exclusive induction of a broad T-cell response
against structural antigens suggests that the most
effective defence against HIV-1 transmission
might require the combination of HIV-1-specific Tcell responses and anti-HIV-specific antibody responses. Our unit is involved in characterizing the
anti HIV-1 T-cell mediated immune responses as
well as in the individuation of the genetic polymorphisms that favour the long term survival of particular HIV-1 infected individuals without sign of immune deterioration (LTNP) and/or that naturally
control viral replication below the level of detection
of the clinical lab tests (Elite controllers= EC)
Main results obtained in 2013
In collaboration with the Unit of Molecular Medicine
led by Dr Roberto Biassoni at the G. Gaslini Institute we characterized a cohort of 80 HIV-1 infected
Natural controllers (41 EC and 39 LTNPs), 175 HIV1 progressors and 111 HIV-1 negative blood
donors for a set of genetic markers involved in
shaping differential immune-responses in autoimmune diseases and chronic infections (snp IL7R/rs987106 A/T, rs987107 C/T, IL28/rs8099917
T/G, IL28/rs2979860 T/C HLA B and C supertyping, HLAC/rs9264942 T/C HLAC/rs67384697 G/miRNA 148 a/b in combination with a complete
KIR genotype). All the genetic tests have been performed and a database containing clinical and routine laboratory analysis as well as the results
obtained by our genetic screening have been realized to perform the necessary statistical evaluations. A screening system of statistical evaluation
based on Chi square and fisher exact test have
been set up for fishing out the most significant variations in markers distribution. Regarding both IL7 R
and IL-28 snp the data show a trend for a significant increased only in Primary HIV-1 infected individuals that deserve further investigation. On the
contrary both HLA-C associates markers and Bw4
I80 supratype are significantly increased in NC.
More interestingly a few KIR genes are significantly
overrepresented only in EC individuals. Given the
existing linkage disequilibrium (LD) from HLA genes
as well as from KIR genes a more complex analysis that take in consideration LD and epistatic models is under evaluation.
Mauro S. Malnati
Protein engineering and therapeutics
We focus most of our efforts on the production
and development of HIV-1 entry inhibitors based
on derivatives of CCL5/RANTES (a natural ligand
of CCR5, the major HIV-1 co-receptor) acting as
CCR5 antagonists. In the context of competitive
grants from the EU, the NIH and the Italian Ministry of Health, potent anti-HIV-1 full-length CCL5
mutants and short peptides have been developed
for their prospective implementation as mucosal
microbicides. We are involved also in the “live microbicides” field, an approach based on the engineering of human commensal bacteria (e.g., lactobacilli) to produce anti-HIV-1 proteins. Lactobacilli were successfully implemented also as a
platform to screen conceptually novel CCL5 mutants. By fusing our best CCL5 full-length derivative with an HIV-1 fusion inhibitor, we recently obtained a crossclade CCR5 antagonist with
low/sub-picomolar IC50% activity. Furthermore,
the combination of many different HIV-1 inhibitors
with full-length or short peptide CCL5 derivatives
presented full additivity or synergism in vitro. Our
CCL5 derivatives will be tested also on other
pathologies where CCL5 is of major relevance
(e.g., inflammation and cancer). For our work on
CCL5 derivatives, Massimiliano Secchi received
the “G.B. Rossi prize 2013” by the Italian Association to fight AIDS (ANLAIDS).
In a different research area (co-directed with Antonio Siccardi), we investigate the role of IgE as anti-tumor agent, studies empowered by our unique
collection of IgE-related transgenic mice. We
found that IgE is a potent adjuvant in anti-tumor
vaccination and that Fc ε RI (the high affinity receptor for IgE) is the key mediator of the anti-tumor effect. This system was evolved by recruiting
a truncated version of membrane IgE (tmIgE), capable to bind and activate Fc ε RI, using a safe
recombinant MVA (modified vaccinia virus Ankara)
engineered to express tmIgE. We also investigated the role of IgE as natural anti-tumor surveillant,
a long-lasting research project producing exciting
results being assembled for publication.
Finally, we plan to implement commensal bacteria
engineering to combat various worldwide pathological threats (such as HIV-1, allergy and avian influenza).
Luca Vangelista
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Figure 21. Rational design
of a sub-picomolar HIV-1 inhibitor based
on the fusion between a CCL5
derivative (targeting CCR5 as
antagonist) and C37 (targeting gp41).
γδ T cells in innate and adaptive immunity
Targeting ADAM10 and ERp5 in Hodgkin and non Hodgkin lymphomas
CD8+T and γδ T cells, mediators of stress-related
immunity, respond through the NKG2D receptor to
NKG2D-ligands (NKG2D-L), as the MHC class-I related molecules MICA/B and the UL16-binding
proteins 1-4 (ULBPs). We reported that circulating
γδT lymphocytes in chronic lymphocytic leukemia
and non Hodgkin lymphomas (NHL), react to autologous cancer cells expressing MICA or ULBPs
and this correlates with disease stage and progression (Blood 2007, 109:2078). Due to NF-κB
activation via NKG2D, leading to transcription of
Bcl-xL antiapoptotic protein, γδ T cells are quite resistant to apoptosis (Int J Cancer 2011,129:387).
NKG2D-L can be upregulated in vivo by all-transretinoic acid or sodium valproate (VPA) (Leukemia
2009, 23:642); however, NKG2D-L can be shed,
interact with NKG2D on effector lymphocytes and
hinder the recognition of tumor cells. Shedding of
soluble (s) MIC-A depends on the thiol isomerase
ERp5and the disintegrins ADAM10/17, which also
cleave ULPBs. In Hodgkin’s lymphoma (HL), the LN
stroma displayed in situ high levels of ERp5 and
ADAM10, mainly in Reed-Sternberg (RS) and in
LN-mesenchymal stromal cells (MSC), and sMICA and sULBP3 were detectable in patients’sera.
Upon co-culture with LNMSC, CD8+T and γδ T
cells reduced their cytolytic activity against NKG2DL+ targets, due to TGFβ produced by LNMSC
and able to down-regulate the expression of
NKG2D. In addition, CD8+T and γδ T cells from
the lymph nodes of cHL patients co-cultured with
LNMSC, underwent TGF-mediated down regulation of NKG2D (Blood 2012, 1196:1479). Of note,
exposure of LNMSC to aminobisphosphonates
prevented the effects of LNMSC on γδ T cell function (Hematologica 2014, 99:131). We are currently preparing specific ADAM10/ADAM17 inhibitors in order to prevent sNKG2D-L; preliminary
results of experiments with siRNA point to a predominant role of ADAM10 vs ADAM17 in RS cells
and at least one specific ADAM10 inhibitor has
been synthesized able to interfere with the sheddase activity. We are also preparing specific peptides to inhibit ERp5 enzymatic activity
Maria Raffaella Zocchi
149
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Research Units
Immunobiology of HIV
CCR5 modulation as target to block HIV transmission
Our Unit focuses on the structure-immunogenicity
applied to the host-virus relationship. The last few
years have provided documentary evidence of the
existence of subjects who, despite multiple exposures to HIV-1, remain seronegative (referred to as
ESN). The possibility that some of these subjects
may be “spontaneously vaccinated/cured” cannot
be excluded, and so the study of their antiviral response may reveal as yet unknown resistance
mechanisms that may be reproducible in others.
The analyses the immune factors involved in immune controls could be extremely relevant to generate strategies able to prevent HIV transmission.
CCR5 cellular protein is one the main coreceptors
for HIV and CCR5 downregulating immunoglobulins were found in sera and mucosal samples in
ESN suggesting a role for such antibodies in controlling viral replication in vivo. Natural antibodies
(Abs) to CCR5 showed HIV-blocking properties,
both in CD4+ T lymphocytes and in CCR5 transfected cells lines. It is very relevant to underline that
the mechanism of action of these Abs is different
from that reported for other CCR5 specific mole-
cules. Natural Abs to CCR5 specifically inhibit HIV
replication by inducing a full and long lasting CCR5
downregulation with a very slow kinetic. Indeed, in
an experimental BalB/c mouse model, full in vivo
CCR5 downregulation, as well as receptor backregulation, follow a very slow kinetics (similar to that
induced by Abs in humans) that was gradually recovered in 4 weeks after immunization. We found
that anti-CCR5-ECL1 Abs induce receptor internalization and recycling mediated by G-protein dependent ERK activity. These events require
β-arrestins, which may couple ligand-activated receptors to clathrin, and lead to a cytoplasmatic
CCR5 accumulation with consequent activation of
ERK1/2. Our findings suggest that natural anti
CCR5 antibodies, bind receptor and reach CCR5
intracellularly, thus inducing a degradation of the
receptor, which prevent interaction with HIV. Thus,
our research is aimed at creating such immune
barrier by targeting the host rather than the virus
establishing a durable elimination of CCR5.
Lucia Lopalco
AIDS immunopathogenesis Unit
Central theme of our Unit is the regulation of HIV-1
replication by host factors, primarily of immunological nature. In this scenario, in this year we have
been focusing our research primarily on the topics
listed below.
Macrophage polarization and HIV-1 infection. After
our original observation that that both M1 and M2
polarized monocyte-derived macrophages (MDM)
support less efficiently virus propagation, we have
observed that M2-MDM upregulate selectively the
surface molecule DC-SIGN, a capture receptor for
HIV involved in trans-infection of CD4+ T cells,
which is, conversely, downregulated in M1-MDM.
On the other hand, M1-MDM showed the upregulation of APOBEC-3A, an intracellular factor that
might contribute to the retroviral restriction in these
cells.
Identification of host factors influencing HIV-1 replication in the female genital tract. We have established a model of infection of human cervical tissue
explants (CTE) established form women undergoing hysterectomy for benign tumors. Tissues are
subdivided in small regular 2-mm3 blocks and infected in the absence of exogenous stimulation by
mitogens or cytokines. By a post-hoc analysis we
have observed that only CTE established form
women in their secretory phase of the menstrual
cycle were productively infected, implying a direct
or indirect contribution of progesterone to HIV replication in this anatomical tract. Our findings support
epidemiological evidence of a higher susceptibility
of women in this phase of the menstrual cycle to
become infected by HIV-1 as well as of transmitting
the virus to their partners.
Genetic studies on LTNP. As a follow-up of the
concerted effort of a European consortium
(“GISHEAL”) investigating the genetic background
of individuals with a “long-term nonprogressing”
(LTNP) phenotype (defined as maintenance of
>500 CD4+ T cells/µl for >8 years of infection and
good healthy conditions without ever receiving antiretroviral therapy) we have participated to a metanalysis study involving 6,300 infected and 7,200
uninfected control individuals. The results of the
analysis indicated that, except for the Δ-32 deletion mutation in CCR5, there is no contribution of
genetic factors to HIV-1 acquisition.
Guido Poli
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Biocrystallography Unit
The Biocrystallography Unit is devoted to the biochemical, structural and functional characterization of macromolecules of biomedical interest.
The main areas of activity include:
a) Infectious diseases
We have a longstanding interest in the study of
nucleotide-metabolizing enzymes for the rational
development of drugs. We showed that enzymes
with nucleosidase (NH) activity are essential for
the life cycle of trypanosomes, parasites that
cause life-threatening pathologies such as sleeping sickness or Chagas’ disease. We recently determined the crystal structure of the purine-specific NH from Trypanosoma brucei bound to several
inhibitors, including a compound that eradicates
parasites in infection models. Using a similar approach, we are also identifying targets for novel
antibiotics against multidrug-resistant Staphylococcus aureus and Mycobacterium tuberculosis.
b) Cancer
We are characterizing the role of a novel cyclindependent kinase in the invasiveness of glioblastoma multiforme, the deadliest brain tumor. The
goal is to determine the crystal structure of the
enzyme, and to use a combination of in silico and
in vitro methodologies to identify selective, tightbinding inhibitors. These compounds may reduce
the aggressiveness of the neoplasy, and enhance
the success of surgical removal. We are also
characterizing the structures of B-cell receptors
involved in the pathogenesis of chronic lymphocytic leukemia, in order to develop novel, effective
therapeutic strategies.
c) Autoimmune diseases
We are studying the molecular mechanisms underlying the immunomodulatory activity of fingolimod, a prodrug that upon phosphorylation by
sphingosine kinases prevents the egress of T
lymphocytes from the lymph nodes. This compound can be administered orally, and is effective
in reducing the progress of disability in patients affected by multiple sclerosis. We are currently determining the crystal structures of both the activatory enzyme SPK2, and the five members of the
sphingosine 1-phosphate receptor family. These
G-protein coupled receptors are expressed differentially in tissues, and the structures will allow the
design of selective agonists to enhance the immune suppression, and reduce systemic adverse
effects in treated patients.
Massimo Degano
Figure 22. Active site of the
IAGNH enzyme from T.
brucei bound to a nanomolar
inhibitor. Knowledge of the
active site cavity features
(green transparent surface)
allows the modification of the
compound (yellow sticks) to
enhance its activity.
151
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Research Units
Cellular immunology Unit
Harnessing the immune system against malignancies
Our research is focused on defining the dynamic
interactions between a growing tumor (i.e., transformed cells and surrounding stroma) and the immune system. This knowledge is then implemented to identify means whereby induce a therapeutic tumor-specific immune response.
We have recently focused our research on cancer
stem cells (CSCs) as drivers of prostate cancer
development and progression. From transgenic
adenocarcinoma of the mouse prostate (TRAMP)
mice harboring oncogene-driven prostate cancer,
we have established stage-specific prostate CSC
lines that are endowed with the critical features
expected from malignant bona fide CSCs, namely, self-renewal, multipotency, and tumorigenicity.
Long-term population analyses ruled out the possibility that our CSCs were transient amplifying
progenitors. Transcriptome analysis showed that
genes upregulated in each stage-specific CSC
were significantly associated with distinct clinical
subgroups of prostate cancer patients, thus indicating that mouse CSCs define human prostate
cancer progression signatures.
Although CSCs were killed in vitro by NK cells and
cytotoxic T lymphocytes (CTLs), they generated tumors when injected in immunocompetent mice,
thus suggesting they possess mechanisms of immune evasion. We are investigating this issue.
In the same model as well as in the transplantable
B16 melanoma, we have also assessed the ability
of dendritic cell-based vaccines to induce a longlasting tumor-specific CTL response in either prophylactic or therapeutic settings. Our results
indicate that booster vaccinations are indispensable in prophylactic settings to sustain the pool of
vaccine-induced central memory T cells, which associate with potent protection against tumor development. Conversely, booster vaccinations are
detrimental in tumor-bearing subjects because
negatively impact on central memory T cells. Thus,
our results suggest that the need for boosting
should be evaluated in any given cancer patient
depending on the state of the disease.
Matteo Bellone
Dynamics of immune responses Unit
Our research program seeks to dissect the complex dynamics of host-virus interactions with a
particular focus on the development and function
of adaptive immune responses. Since it is still beyond the reach of even the most sophisticated in
vitro methodology to simulate the complex interplay of physical, cellular, biochemical, and other
factors that influence cell behavior in microvessels
and interstitial tissues, we make use of intravital
microscopy. This technique is complemented by
more traditional molecular, cellular and histological
approaches, thus characterizing host-virus interactions at the molecular-, single cell- and whole
animal-level.
Ongoing projects in the lab include:
1) To understand how virus-specific effector CD8
T cells migrate to the liver and recognize intrahepatic antigens in the context of viral hepatitis
and hepatocellular carcinoma.
2) To provide the first complete in vivo imaging
survey of virus-specific B cell activation, from
the first minutes of viral entry into lymph nodes
to the generation of high affinity neutralizing antibody-secreting cells and to identify virus-induced mechanisms interfering with neutralizing
antibody responses.
3) To characterize the newly discovered adjuvant
activity of bisphosphonates
4) To assess the role of antigenic stimulation in
chronic lymphocytic leukemia pathogenesis.
Matteo Iannacone
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Figure 23. Confocal micrograph of a mouse popliteal lymph node cross-section. CD169+ macrophages are
highlighted in red, B220+ B cells in white and LCMV-infected cells in green. Scale bar represents 200 μm.
Emerging bacterial pathogens Unit
Fighting drug resistant Tuberculosis and other multidrug resistant
nosocomial pathogens
Drug resistant (DR) bacteria are an emerging
plague worldwide. Our research program seeks
to understand the mechanisms leading to DR and
increased bacterial virulence in two main areas:
Tuberculosis (TB) and Health Care Associated DR
Pathogens (HCAP).
TB: The future universal regimens for TB and
DRTB, will be based on three main drugs(rifampicin, moxifloxacyn and pyrazinamide). By
Next Generation Sequencing of a large collection
of TB strains we have identified panels of genes
and mutations associated to resistance to specific classes of antibiotics. For Pyrazinamide we
have mapped the mutations on pncA gene and
shown that resequencing of this gene is the most
accurate method to predict resistance to this
drug. We showed that not all mutations confer the
same DR level.
The progress in biomarkers research has lagged
behind that of tuberculosis diagnostics: we have
identified and validated a specific signature based
on circulating miRNAs able to discriminate people
with active TB from healthy controls.
Small non-coding RNAs (sRNAs) play an important role in the stress response and the pathogenicity of many bacteria. We identified and published sRNAs in M. tuberculosis. To better understand their role in the response to stress conditions induced by antibiotics, RNAseq approach
has been used to provide novel insights in mycobacterial trascriptomic networks (sRNA + mRNA) and showed that selective sRNAs are expressed during exposure to ofloxacin.
HCAP: We have previously shown that the MRSA
clone ST22-IV is the predominant MRSA clone in
OSR. We have identified as factor contributing to
his success several virulence properties including
biofilm production, growth rate and invasiveness.
153
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Research Units
KPC producers Gram negative bacteria have
been a major cause of nosocomial infections in
2013. We identified 2 main epidemic KPC-Klebsiella pneumoniae clones, ST512 and ST258. We
showed that both clones are able to transfer the
blaKPC gene horizontally to E. coli. The spread of
such resistance to other species is worrisome
and must be closely monitored.
C. difficile is a major cause of nosocomial diarrhea. We demonstrated that defensins (HNP-1
HD5) may play an important role during the infection disrupting the bacterial cell membrane.
Daniela Maria Cirillo
Experimental immunology Unit
T cells restricted for CD1 and MHC molecules in the immunosurveillance
of tumors
Our research proceeds along two main complementary axis addressing the role of T-cell immune
responses in the tumor immunesurveillance.
1. Development and function of CD1-restricted T
cells specific for lipid antigens
We investigate the development and function of
CD1d-restricted invariant (i)NKT cells, a unique
subset of T lymphocytes with innate effector
functions that plays and important role in tumor
immune surveillance. Specific miRNAs that control the development and effector functions of
iNKT cells were identified and the effects of the
modulation of their targets are being investigated. We have also gained further mechanistic insights into the iNKT-cell control of pro-tumor
macrophages infiltrating the prostate cancer developing in the TRAMP transgenic mouse model.
Furthermore, we have established a clear prognostic and functional role for the iNKT/CD1d axis
in CLL, both in patients and in the TCL1 mouse
transgenic model.
A second type of CD1 restricted T cells recognizes endogenous lipid antigens presented by
CD1a, b, c, which are not expressed in mice. We
have characterized a new lipid antigen that is enriched in acute leukemia and is recognized by
CD1c-restricted T cells with anti-leukemia activity.
T cells with comparable reactivity develop in
transgenic mice expressing human CD1c, providing a valuable pre-clinical model to study this
newly discovered T cell response.
2. Definition of the somatically mutated T cell-defined antigen landscape of colorectal cancer
We have further implemented an integrated platform based on next generation sequencing and
reverse immunology, to identify somatically mutated genes expressed by colorectal cancer (CRC)
and CRC cancer stem cells (CSC), and to define
the immunogenicity of the corresponding unique
epitopes recognized by both CD4+ and CD8+ T
cells.
Paolo Dellabona & Giulia Casorati
Infection and cystic fibrosis Unit
Host-pathogen interactions in cystic fibrosis: implications for
pathogenesis and therapy
The goal of our program is to dissect hostpathogen interactions during persistent infection
in cystic fibrosis (CF) with the aim of devising new
therapeutic approaches to treat respiratory infections.
1. Cellular and molecular mechanisms involved in
host-pathogen interactions. Polymicrobial infections by Pseudomonas aeruginosa, Staphylococcus aureus and Burkholderia cenocepacia are difficult to treat and responsible for the decline of
lung function in CF. Taking advantage of wholegenome analysis, human specimens and unique
mouse model of infection, developed within the
lab, we have recently demonstrated that these
pathogens adapt to the CF niche and often coexist influencing the CF pathogenesis. A repertoire of adaptive changes in the bacterial genome
accumulated with the length of persistence in the
CF airways and affected the persistent lifestyle of
the pathogens in chronic infection. CF bacterial
patho-adaptive variants revisit their interaction with
host by dampening the inflammatory response
and activating pathways relevant for damage and
remodelling process. Pathological analysis of
murine lungs infected with adaptive strains
showed advanced chronic pulmonary disease,
inflammation and mucus secretory cells hyperplasia, mimicking many key features of pulmonary
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
exacerbation observed in CF patients. This new
knowledge will favor much-needed insight into
aspects of bacteria/CF interaction and lead to
novel biomarkers and therapeutic approaches.
2. Evaluation of novel molecules for treating respiratory infection and inflammation. Murine model
for acute and chronic infection, along with mice
genetically modified for the Cftr gene, are a key
asset in CF research. The CF Animal Core Facility
(CFaCore) provides murine models and supports
the CF community testing novel therapeutic mole-
cules. The aim is to favor the translation of basic
research projects into pre-clinical applications.
Pre-clinical murine models of P. aeruginosa
chronic lung infections have been used to
demonstrate that the flucytosine, an anti-virulence
drug discovered by a drug-repurposing approach, and myriocin, an inhibitor of the sphingolipids, are potential therapeutic tools in controlling infection and inflammation supporting further
development in translational applications.
Alessandra Bragonzi
Figure 24. Non-CF and CF human lungs stained by AB-PAS for globet cells.
Leukocyte biology Unit
Harnessing oncogene-induced responses in liver tumorigenesis to identify
novel therapeutic strategies
Aberrant DNA replication induced by deregulated
or excessive proliferative stimuli evokes a “replicative stress response” leading to cell cycle restriction and/or apoptosis. This robust fail-safe mechanism is eventually bypassed by transformed
cells, due to ill-defined epistatic interactions. The
COP9 Signalosome (CSN) is an evolutionarily
conserved regulator of Cullin Ring Ligases
(CRLs), the largest family of ubiquitin ligases in
metazoans. Conditional inactivation of the CSN in
several tissues leads to activation of S- or G2phase checkpoints resulting in irreversible cell cycle arrest and cell death. Herein we ablated
COPS5, the CSN’s catalyitc subunit, in the liver,
to investigate its role in cell cycle re-entry by differ-
entiated hepatocytes. Lack of COPS5 in regenerating livers causes substantial replicative stress,
which triggers a CDKN2A-dependent genetic
program leading to cell cycle arrest, polyploidy
and apoptosis. These outcomes are phenocopied by acute overexpression of c-Myc in
COPS5 null hepatocytes of adult mice. We propose that combined control of proto-oncogene
product levels and proteins involved in DNA replication origin licensing may explain the deleterious
consequences of CSN inactivation in regenerating livers and give insight into the pathogenic role
of the frequently observed overexpression of the
CSN in hepatocellular carcinoma.
Ruggero Pardi
155
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Research Units
Figure 25. DNA re-replication in CSN-deficient hepatocytes in vivo. Shown is a DNA fiber undergoing aberrant rereplication, as determined by the merged fluorochromes. Arrows denote stalled replication forks.
Lymphocyte activation Unit
Understanding the cellular and molecular mechanisms at the basis of
adaptive T cell immunity
Our group is interested in the cellular and molecular events controlling CD4 and CD8 T cell homeostasis, activation, proliferation, survival and differentiation. We take advantage of primary T cell cultures, and predictive murine models allowing the
tracking of antigen-specific T cells. Ongoing research activities focus on the TCR-induced intracellular signaling events impacting on T cell proliferation and differentiation, and on strategies to
ameliorate T-cell-mediated responses to solid tumors. Over the past year we have analyzed the
impact of TSC1 deletion in mouse T cell in vitro
and in vivo and also in human T cells, and found
that this unbalances the control of the mammalian
target Of Rapamycin Complex 1 (mTORC1) and
mTORC2, and together with that proper T cell
homeostasis. We also characterized immune responsiveness of patients with heterozygous
germline mutations of TSC1 to start understanding functional consequences of TSC1 loss in humans.In addition, to ameliorate protective T cell
immunity we have exploited the engineering of T
cells with TCR directed to tumor-associated antigen and to minor histocompatibility antigen, in
combinatorial adoptive and active immunotherapy
in the Transgenic Adenocarcinoma of the Mouse
Prostate cancer (TRAMP) model. We are currently
testing additional combination, including vascular
targeting strategies to envisage clinical translation
of the defined approach for the immuno-therapy
of refractory solid tumors.
Anna Mondino
Tumor immunology Unit
Role of the different CD4+ T cell subsets in tumor immunity
CD4+ T helper (Th) cells exist in several subsets,
such as Th1, Th2, Th17 and Th22, which are defined based on the profile of cytokines produced
(IFN-γ for Th1; IL-4, IL-5 and IL-13 for Th2; IL-17
and IL-22 for Th17; and IL-22, IL-13 and TNF-α
for Th22, respectively). CD4+ T cells are frequently found within tumor immune infiltrates and it is
now well established that infiltration by Th1 cells
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
associates with favorable clinical outcome while
predominant Th2 infiltration is mostly associated
with tumor progression. Conflicting results are reported for the Th17 subset, depending on the tumor studied, and very little is known about Th22
cells, which have been recently identified as a independent Th subset. Polarization towards one or
another CD4+ Th cell subset depends on the cytokine(s) milieu present in the tumor and in draining lymph nodes, where CD4+ T cell priming occurs. Thus, the network of cytokine/chemokine in
the tumor microenvironment dictates polarization
of CD4+ T cells towards the different subsets that
in turn, through cytokine release, may further condition the tumor microenvironment with reciprocal
influence. Our studies are focused on pancreatic
cancer and multiple myeloma (MM). Specific aims
are: a) to evaluate tumor infiltrating CD4+ T cell
subsets and to define possible correlation be-
tween the features of the Th subsets identified
and the clinical outcome (i.e., predictive markers)
and to study b) cells and mechanisms dictating
Th polarization and c) how the different CD4+ T
cell subsets exert pro- versus anti-tumor activity in
these pathologies. Our studies are conducted in
collaboration with surgeons, clinical oncologists
and pathologists of the Institute. In the last year
we focused on the study of the relevance of the
different Th subsets in both peripheral blood and
bone marrow aspirate of MM patients with
asymptomatic disease, MM patients at diagnosis
and MM patients with relapsed/refractory disease. We also continued experiments to deepen
our understanding of the cells and factors involved in driving Th2-type inflammation in pancreatic cancer.
Maria Pia Protti
Viral evolution and transmission Unit
Antigenic and phenotypic characterisation of HIV-1 variants in
transmission and disease progression as target for vaccine development
New immunogens capable of inducing broadly
neutralizing antibodies (bNAbs) are a priority in
HIV-1 vaccine research. We hypothesized that viral variants from patients, who display bNAb responses, may harbor specific Env structures that
could elicit bNAbs if formulated into an appropriate vaccine immunogen. Thus, we studied the kinetics of Nabs and antibodies reactive to HIV-1
Env constant and variable regions as well as
childhood vaccine antigens from birth on for five
years of follow up in infected children with rapid or
slow disease progression.
We show that newborns display antibodies directed towards HIV-1 immunodominant, constant epitopes, however, antibodies do not neutralize the
transmitted virus. The Nab response directed to
the autologous transmitted/founder virus tends to
increase during follow up, induces continuous
emergence of escape variants and appears in
parallel with antibody responses to peptides representing the Env variable region of transmitted/
founder virus, suggesting that these might contribute to the autologous Nabs response. Interestingly, Nabs to heterologous viruses may be devel-
oped within 2 years of age, but their subsequent
increase in potency and breadth is a trait of slow
progressors. However, kinetics of antibody responses to the viral immunodominant constant
and childhood vaccination antigens is preserved
and independent of disease progression. Thus,
immunocompetence appears essential for the
ability to mature the Nab response. Furthermore,
transmitted/founder viruses of slow progressors
may represent an attractive target for vaccine design, which aims to induce cross-Nabs, and
therefore we selected the Env of two transmitted/founder viruses to produce Env gp140 trimers
for vaccination in rabbits. Comparison of their immunogenicity side-by-side with other five gp140
trimers selected from adult infected individuals
showed that all groups of immunized rabbits develop antibody reactivity to Env, which is followed
by Nabs against heterologous HIV-1. Thus, we
have selected new Env from transmitted/founder
viruses of children suitable for immunization in animals to study protection from transmission.
Gabriella Scarlatti
157
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Research Units
Viral pathogens and biosafety Unit
Restriction factors of Immunodeficiency virus (HIV) and Influenza A virus
replication: role of tripartite motif containing protein 22 (TRIM22)
Replication of the human immunodeficiency virus
(HIV) is heavily dependent on components of the
host cell machinery. These may encompass active resistance governed by innate immune circuits that aim at eliminating pathogen burden and
collectively defined as “restriction factors (RF)”. In
addition, a group of constitutively active cellular
components can curtail the levels of pathogen
replication (“set point factors, SPF”). We hypothesize that these latter enable the host to tolerate infection by attenuating the cytopathic effects of
unrestricted replication. While viruses almost invariably have developed countermeasures to cellular RF, some, but not all, SPF appear to be targeted for viral inactivation. The activities of both
host cell viral resistance factors contribute to determining the capacity of a virus to establish a
pathogenic infection in the host.
We have previously shown that the interferon-inducible Tripartite Motif-22 (TRIM22) acts as SPF
for HIV-1 by inhibiting HIV-1 replication by acting
at the transcriptionl level (A. Kajaste-Rudnitski et
al., J. Virology 2011). We are currently determin-
ing the molecular mechanisms by which TRIM22
exerts these functions and have identified two single nucleotide polymorphisms (SNPs) in the coding region of TRIM22 and located in the coiledcoil domain of the protein that enhance its capacity to inhibit HIV transcription. Furthermore, we
have reported that these TRIM22 isoforms are associated with the severity of HIV disease (S.
Ghezzi et al., AIDS 2013).
In addition to HIV-1, we have demonstrated that
TRIM22 can also restrict influenza A virus (IAV) infection (A. Di Pietro et al., J. Virology 2013). In this
case TRIM22 mechanism of restriction relies on
its E3-ubiquitin ligase activity upon interaction with
the viral nucleoprotein that promotes its degradation in a proteasome-dependent fashion. We are
currently studying the potential role of TRIM22 in
the acquisition of nucleoprotein adaptive mutations during human-to-human viral spreading also
in the context of understanding the nature of pandemic IAV infection.
Elisa Vicenzi
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Clinical Research Units
Management and antiretroviral treatment of HIV infection
Clinical Trial Unit (CTU) is a clinical research unit at
the Department of Infectious Diseases, focused
on addressing clinically relevant questions that
may improve HIV patient care.
Cohort Studies: CTU is collaborating with national
and international cohorts studies through the Infectious Diseases Database (IDD-OSR) with the
aim to conduct epidemiological research on the
prognosis and outcome of HIV-infected people
from across Italy and Europe including adults,
children and pregnant women. The research is focus on scientific questions requiring a large sample size of patients which the contributing cohorts
cannot answer individually. The IDD-OSR is an
observational, longitudinal, clinical database on
adult patients receiving primary HIV care at the
Clinic Infectious Diseases. This database was developed in 1999. IDD-OSR manage a wide set of
data of 8821 recorded patients.
Clinical Trials: CTU is involved in conducting and
coordinating national and international industry
sponsored phase II-IV clinical trials. Main activities
contribute to the registration of new compounds,
new indications and to the organization of early
access program for patients with limited therapeutic options.
Randomised clinical trials are focused on two research areas:
1) Development of new antiretroviral strategies in
order to overcome HIV resistance and to favour
patient quality of life. In the next tree years we will
study new drugs for the treatment of naïve and
experienced patients; we will evaluate efficacy
and safety of simplification strategies in patients
with suppressed viral replication, salvage strategies in patients resistant to all the standard therapies holding regimens based on lamivudine
monotherapy in failing patients harbouring the
M184V mutation
2) Long-esposure to antiretroviral drugs and HIV
resistance are frequently associated with longterm non HIV complications such as cardiovascular risk, cirrosis, cancer, diabetes. In the next three
years CTU will contribute to evaluate pathogenesis, diagnosis, therapy and prevention of type 2
diabetes during HIV infection. Research activity of
CTU led to 45 scientific publications during 2013.
Antonella Castagna
Neurovirology
Central nervous system (CNS) HIV infection. HIV brain
infection may be associated with neurocognitive impairment (NCI); in addition CNS cells are a potential
viral reservoir. We are characterizing mild NCI by radiological and cerebrospinal fluid (CSF) and blood
markers. In neuro-asymptomatic untreated patients,
MR-DTI showed white matter microstructural alterations that did not correlate with NCI, suggesting that
NCI may be associated to HIV-unrelated conditions.
Alterations did not improve after years of therapy, providing a marker of subclinical tissue injury in chronic infection. By the study of cases of “CSF viral escape”, i.e., CSF HIV replication despite no or low systemic replication, we identified different HIV populations between the two compartments, indicating that
HIV may evolve autonomously in CNS and supporting
the hypothesis of CNS as virus reservoir.
Progressive multifocal leukoencephalopathy (PML).
PML is a progressive demyelinating disease caused
by JC virus (JCV) reactivation and infection of oligodendrocytes that affects patients with impaired immunity or taking immunomodulant drugs. We are investigating a pathogenesis model by which JCV es-
capes the host immune system by selection of mutations in its major surface protein VP1. We identified several immunogenic VP1 peptides binding with
high affinity with most HLA-DRB1 molecules and
showed ex-vivo IFN-γ Elispot responses against wildtype, but not mutated peptides. Similarly, analysis
of serum from PML patients revealed the presence
of neutralizing antibodies against wild-type, but not
mutated viruses. These findings may be relevant for
developing immune-based treatments and vaccines.
Chronic inflammation in HIV infection. Chronic diseases are a major cause of mortality and disability
in treated chronic HIV infection and are associated
with persistent low-grade inflammation. Following a
moderate intensity physical exercise program we observed significant improvements of plasma IL-6,
hsCRP, D-dimer, IL-18 and myostatin, and of
CD8+/CD38+/HLA-DR+ cell frequencies, in parallel with improvement of morphometric measures, and
blood lipids. These findings are prompting us to develop protocols for exercise as treatment of chronic inflammation in HIV infection.
Paola Cinque
159
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Clinical Research Units
Study and treatment of hepatotropic viruses related
diseases
Dynamics of mixed HCV infection in different compartments, plasma and
peripheral blood mononuclear cells, during treatment with Peg-IFN plus
ribavirin in HIV/HCV coinfected patients: possible implication for
treatment in the era of direct antivirals
According to the World Health Organization, 130
to 170 million people are persistently infected with
hepatitis C virus (HCV) and are at risk of developing severe liver disease and hepatocellular carcinoma. HCV is an enveloped, positive strand RNA
virus belonging to the Hepacivirus genus in the
Flaviviridae family. Seven confirmed genotypes
are generally distinguished by phylogenetic methods and pair-wise distance calculations. It is well
known that antiviral treatment with pegylated interferon (P) plus ribavirin (R) at initiation of HCV infection achieves sustained virological response
(SVR) rates of 30-50% in HIV/HCV coinfected individuals, depending by the infecting genotype.
In clinical trials a number of direct antivirals (DA) in
association or not with P-R (figure1)showing a
dramatic increase of SVR in HCV mono infection
as in HIV/HCV coinfection, will revolutionize the
HCV treatment.Virological studies suggested that
drug resistance variants to DA may pre-exist as
minor quasispecies and can serve as a rapid
source of drug resistance.
We have studied this issue and showed that natural resistant strain may revert to wild type, and
that resistant strain may be present in liver compartment irrespective of wild type in plasma compartment. These ourfindings hampered the importance to perform the genotyping resistanceassay
beforeanti-HCV treatment.
The majority of patients attending our Department,need new drugs treatment becausefailed PR treatment. In this context, it is unknown the effect of P-R treatment on the virus heterogeneity in
HIV/HCV coinfection. We investigated the viral
population by ultra deep pyrosequencing before
and during HCV treatment with P-R and surprisingly we found a high frequency of mixed HCV
genotype with alternance of different genotypes
inplasma and peripheral blood mononuclear cells.
Failure to P-R treatment was associated with
mixed infection in plasma compartment.
These findings may have important clinical implications in light of the new therapeutic approaches
in HIV/HCV coinfected individuals that may harbour unrecognised mixed infection, suggesting
that triple therapy including DA could be ineffective in individuals with mixed genotypes.
Caterina Uberti-Foppa
Figure 26. HCV genome organization and target regions of direct antivirals compounds.
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Vaccine and immunotherapy
Treatment of primary HIV infection
The potential benefit of an early intervention could
pave the way for future therapies aimed at HIV
eradication, are currently widely studied In patient
with primary HIV infection (PHI). An early treatment
could potentially preserve the HIV-specific immune response, thus increasing the chances of a
better control of viral replication.
Examples of HIV-1 positive individuals treated in
PHI who maintain viral suppression when ART is
stopped have received much attention as the
mechanisms behind ‘post-treatment control’
(PTC) might inform strategies for achieving drugfree remission.
The timing and duration of therapy required to induce PTC is unclear, as are host and viral factors
that may contribute. The SPARTAC (Short Pulse
ART at Seroconversion) trial is the largest international randomised study of short-course therapy in
PHI (N Engl J Med. 2013 Jan 17;368(3):207-17)
The impact of therapy at PHI on subsequent viraemia and clinical progression remains a clinically and mechanistically important question. SPARTAC demonstrated clinical benefit and suppression of viraemia with 48 (but not 12) weeks of
short-course ART (PLoS One. 2013 Oct
25;8(10):e78287)
CCR5 is pivotal both as co-receptor for the majority of HIV quasispecies and as part of the inflammatory response cascade, and several authors
suggested a possible role of maraviroc (MVC) as
immune modulator. B-cells compartment is also
impaired since the earliest phases of infection and
these alterations are not restored by ART initiated
during chronic infection (7th IAS Conference on
HIV Pathogenesis, Treatment and Prevention,
Kuala Lumpur, Malaysia, 30 June-3 July 2013;
abs# WEPE449).
We conducted a randomized proof of concept
clinical trial aimed at assessing whether ART intensified with MVC initiated during PHI would be
harnessed to improve immunological and virological parameters (Keystone Symposia: Immune Activation in HIV Infection: Basic Mechanisms and
Clinical Implications. April 3, 2013 - April 8, 2013
- Beaver Run Resort - Breckenridge, Colorado,
USA; abs# 3032).
In addition, we investigated the influence of ART
on the immune system perturbation established in
this early phase of HIV pathogenesis (paper submitted).
Giuseppe Tambussi
Clinical immunopathology and advanced medical
therapeutics Unit
Systemic inflammatory diseases represent a major unmet medical need: despite the growing insight on the molecular basis of the immunological
response, our understanding of the events associated to autoimmunity in each given patient remains scant and the treatment are mainly selected based on empirical knowledge. A more lucid
insight on the molecular events underlying the
pathogenesis of these diseases is required to
identify diagnostic and predictive markers of activity, organ involvement and outcome. In the last
period we have specifically focused on the characterization of clinical features associated with
the prototypic systemic autoimmune disease,
Systemic Lupus Erythematosus (SLE) with attention to the kidney involvement and to the associated pregnancy complications; the identification
and validation of novel markers to assess the activity of systemic large vessel vasculitides,
Takayasu’s arteritis in particular, and the validation
of novel imaging approaches and possibly of
novel criteria to assess disease activity; the immunopathogenesis of fibrosis and vascular damage in systemic sclerosis and associated conditions, with attention to the molecular determinants involved in the leukocytes/endothelial cells/
platelets interaction; among fibroinflammatory
conditions we are also particularly interested in
immunoglobulin G4 (IgG4)-related disease, a recently described immune-mediated disease that
can cause progressive fibrosis and damage of
virtually every organ.
Maria Grazia Sabbadini
161
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Clinical Research Units
Clinical transplant Unit
The main fields of research activities of the Unit
are focused on:
• Islet transplantation (see description in the DRI)
• Chronic allograft nephropathy (CAN) after kidney transplantation
• Cell therapy in living-donors kidney transplantation (The One Study)
CAN
CAN remains the leading cause of late graft loss
after kidney transplantation. Characterized by progressive tubular atrophy and interstitial fibrosis
(TA/IF) as well as microvascular and glomerular
damage in the setting of declining graft function
months to years after transplantation.
• Group 1: patients with normal renal function
• Group 2: patients who underwent kidney transplant and developed a chronic allograft
nephropathy (CAN).
We are now monitoring the following parameters:
1) renal function (eGFR, serum creatinine, urine
exam)
2) kidney biopsies.
3) Immunosuppression level.
4) Cytokine profile and inflammation.
The ONE Study (www.onestudy.org)
This is a large-scale, collaborative project funded
by the Seventh Framework Programme (FP7) of
the European Commission. The consortium is
composed of academic institutions and industrial
partners.
It is aimed to test several distinct purified
haematopoietic immunoregulatory cells as clinical
therapies in solid organ transplantation by initiating
a series of independent clinical trials. The ultimate
goal is the reduction of long-term immunosuppressive therapy.
Reference group trial:
It is aimed to investigate the progression of the
immunological response in living-donor kidney
transplant recipients treated with a standard immunosuppressive regimen.
Cellular therapy group
At San Raffaele it will be based on TR1 cell therapy (MariaGrazia Roncarolo and Manuela
Battaglia). The clinical protocol is under development.
Clinical trials already ongoing:
1. RAD001 multicenter, randomized, open label
study to evaluate the impact of early vs delayed
introduction of everolimus on wound healing in
kidney transplant (NEVERWOUND)
2. A phase 2 multicenter pilot study to assess the
efficacy and safety of reparixin following islet
transplantation.
3. Planned Transition to Sirolimus-based Therapy
Versus Continued Tacrolimus-based Therapy in
Renal Allograft Recipients
4. Pilot study to assess feasibility and safety of
bone-marrow as alternative site in islet transplant.
Antonio Secchi
Pancreatic tumors Unit: immunotherapy
and β cell function substitution
Autologous Islet Transplantation (AIT) is performed
to improve glycaemic control after extended pancreatectomy. In our center, in addition to chronic
pancreatitis, indications for IAT are: grade C pancreatic fistula (treated with completion or left pancreatectomy); total pancreatectomy as an alternative to high-risk anastomosis during pancreaticoduodenectomy; distal pancreatectomy for benign/borderline neoplasm of pancreatic bodyneck. Malignancy is not an exclusion criterion. In
34 transplanted patients, insulin independence
was reached in 44% of cases and 47% had partial graft function. Seventeen IAT recipients had
malignancy (14 had pancreatic or periampullary
adenocarcinoma) and two of them had already liver metastases at surgery. After a median follow-
up of 750 days, thirteen patients were diseasefree and only one developed metastases in the
transplantation site.
Another important result achieved in 2013 was the
first unequivocal successful engraftment of endocrine tissue in the Bone Marrow (BM) in humans.
Four patients who developed diabetes after total
pancreatectomy were candidates for autologous
transplantation of pancreatic islet. Because the patients had contraindications for intraportal infusion,
islets were infused in the BM. In all recipients, islets
engrafted successfully as shown by measurable
post-transplantation C-peptide levels and
histopathological evidence of insulin-producing
cells or molecular markers of endocrine tissue in
BM biopsy samples analyzed during follow-up.
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Thus far, we have recorded no adverse events related to the infusion procedure or the presence of
islets in the BM. Islet function was sustained for the
maximum follow-up of 944 days. The encouraging
results of this pilot study provide new perspectives
in identifying alternative sites for islet infusion in patients with type 1 diabetes.
Gianpaolo Balzano
Gynecological cancers immunology
Human papillomavirus (HPV) infection and cervical cancer
Main field of investigation of the Clinical Research
Group is the correlation between Human Papillomavirus (HPV) and cervical cancer. In cooperation
with the Tumor Immunology Unit we focused on
HPV-18 and found that low frequencies of CD4+
T cells specific for the E6 and E7 proteins are
present in the majority of HPV-18+ CIN patients.
We also found HPV-18-specific CD4+ T cells in
50% of patients tested, irrespective of the presence of HPV-18 in their lesions, suggesting that
HPV-18-responsive patients might have cleared
the infection. Consistent with this hypothesis, we
found that a robust Th1/Th2 immune response
against E7 but not E6 was associated with the
HPV-18- status. On the other hand, a robust
Th1/Th2 immune response against E6 but not
against E7 correlated with lack of relapses. Our
data demonstrate a positive role for anti-HPV-18
E6 and E7 CD4+ T immunity in CIN patients.
Moreover, we found a significantly higher relapse
rate of preneoplastic lesions (CIN2 - CIN3) after
surgical treatment in cases with reduced
CD4,CD8,CD11C,T-bet and GATA-3 in the
cervix. On the other side, high levels of CD4+ and
GATA-3+ in cervical tissues correlated with disease regression. These data strenghten the tight
correlation between immune response and HPVrelated carcinogenesis.Recent experiences of the
group have lead to the publication of interesting
results concerning the correlation between HPV
infection and HPV-induced cervical lesions in graft
recipients; long-term follow up in multi-drug immunosuppressed transplanted women did not
correlate with an increased prevalence of HPV
genital diseases. A recent cooperation with the
AIDS Immunopathogenesis Unit started and preliminary results, already published in outstanding
journals, indicate that productive HIV infection in
female cervical tissue samples is more likely to
occur in the secretive phase of the menstrual cycle. In 2014 a new project of vaginal microbiome
analysis in cases of HPV-correlated cervical intraepithelial neplasia will start.
Ongoing research projects deal with:
• Cervical mucosal immunity;
• HPV DNA identification;
• Analysis of cervical immune subpopulations.
Massimo Origoni
Immunology in liver neoplasms
Chemotherapy associated liver injury and major hepatic resection for
colorectal liver metastases: role of APRI score and endothelin-1 levels. A
prospective study
Chemotherapy associated liver injury (CALI) is
recognized as a risk factor for development of liver failure (LF) following hepatic resection. APRI
score, based on preoperative AST level and
platelet count, has been proposed as a marker of
oxaliplatin induced parenchymal damage in patients affected by liver metastases. Endothelin-1
is a vasocostrictor peptide which might play a significant in PLF pathogenesis, as a mediator of
acute phase shear stress. Aim of this study was
to evaluate correlation between APRI score and
Endothelin-1 level in pre- and postoperative period.
Patients who required major liver resection for
CLM between 1st January 2011 and 31st June
2013 and who had undergone a period of preoperative oxaliplatin based CT entered this prospective study. In all of them preoperative APRI score
was calculated. In all the patients liver function
tests including AST, ALT, bilirubin and PT were
dosed preoperatively and in POD1, 2 and 5, as
well as ET-1 serum levels.
26 patients entered the study. They received
meanly 6 ± 2 cycles of CT with a mean interval of
31 ±5 days from surgery. 13 (50%) were treated
with bevacizumab. 14 of the whole series (53.8%)
underwent right hepatectomy, 4 (15.4%) right trisectionectomy, 6 (23.1%) left hepatectomy and 2
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DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Clinical Research Units
(7.7%) left trisectionectomy. 12 (46.2%) patients
underwent portal vein occlusion before surgery.
Mortality was nil. Morbidity was 38.5%: 4 patients
(15,4%) showed signs of LF. Mean APRI score of
the entire series was 0.59 ± 0.13. Patients developing PLF had a significantly higher APRI score
(0.66 ± 0.11 vs 0.49 ± 0.12, p<0.05), number of
CT cycles (9 ± 2 vs 5 ± 2, p<0.0) and baseline
ET-1 levels (18 ± 4.4 vs 9.7 ± 3.2, p<0.05) compared to others. Pearson analysis showed a sig-
nificant correlation of APRI score with preoperative
and POD2 ET-1 levels and with POD5 ET-1.
Correlation of APRI with pre and postoperative ET1 may reflect parenchymal damage induced by
CT, resulting in a higher baseline risk of LF. Patients with elevated APRI and ET-1 levels should
therefore be evaluated with caution when a major
resection is planned.
Luca Aldrighetti
Obesity and bariatric surgery
Laparoscopic gastric banding for morbid obesity
Laparoscopic adjustable gastric banding (LAGB)
is performed in case of primary obesity with Body
Mass Index (BMI) >40 or BMI >35 with concomitant serious medical obesity-related conditions,
unresponsive to dietary treatment. Preoperative
evaluation included screening for endocrine disease, endoscopic and radiological study of the
upper digestive tract and ultrasound study of the
upper abdomen.
Between June 1996 and December 2013, 450
patients (78 males/372 females, ranging 18-65
years) received LAGB. Mean body weight was
116.0 ± 18.8 Kg (range 90-195 Kg), with a BMI
ranging between 35 and 65.7 (mean 42.8 ± 5.9).
The laparoscopic procedure was completed in
441 patients (98 %). Eight cases (2.4%) had to be
converted to the laparotomic procedure either because of hepatomegaly (1 case) or because of
gastric lesion during the laparoscopic approach
(7 cases). In one patient the procedure was performed with open technique together with ventral
hernia repair.
Michele Paganelli
Clinical hepato-gastroenterology
Manipulation of the gut microbiota in the treatment of chronic intestinal
disorders
The role of the gut microbiota in promoting and
maintaining intestinal inflammation is by now well
recognized and the object of a great deal of speculation and research, both in the basic science
and in the clinical area.
Antibiotics such as ciprofloxacin and metronidazole can be effectively employed in the treatment
of inflammatory bowel disease, but side effects
are common. Both non-adsorbable antibiotics
such as rifaximin and probiotic agents can represent a safer alternative.
Probiotics have been tested in the treatment of ulcerative colitis and Crohn’s disease (both in the
acute phase and in the maintenance of remission)
with variable but promising results. The choice of
the specific probiotic agent is a critical point because the mechanisms of action of the various
Lactobacillus strains, Bifidobacteria or yeasts
such as Saccharomyces boulardii are quite different. To further expand our previous published experience in this area, we are currently evaluating
the precise role of single probiotic agents, probiotic mixtures and rifaximin as well as symbiotics
(combinations of prebiotics and probiotics) in the
short and longterm treatment of chronic intestinal
disorders both of overt inflammatory nature (ulcerative colitis and Crohn’s disease) and where microscopic inflammation may have a pathogenetic
role (microscopic colitis, irritable bowel syndrome). In addition we are endeavouring to identify and develop proper study protocols in order to
evaluate the efficacy of probiotic agents in clinical
trials carried out according to a correct methodology able to generate sound evidence-based data.
Mario Guslandi
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Digestive pathophysiology
The gastro-esophageal-laryngopharyngeal reflux: from diagnosis to
therapy
Gastroesophageal reflux disease (GERD) is defined as a condition that develops when reflux of
stomach contents causes troublesome symptoms and/or complications. The manifestations of
GERD are classically described as heartburn and
reflux, which are often referred to as “typical
GERD”. However, GERD may also present atypically and is referred to as extraesophageal syndrome. Common extraesophageal manifestations
are hoarseness, globus, throat clearing, and
cough; many evidences show that the gastroesophageal reflux (GERD) may play a pivotal role
in the pathogenesis of the symptoms the so
called laryngopharyngeal Reflux (LPR).
Diagnostic approach to patients with extraesophageal reflux disease involved the use of insensitive tools, which have hampered the ability to
correctly identify patients at risk. In fact, empiric
trial using proton pump inhibitors (PPI) is still the
recommended initial approach to the patients
suspected of having reflux as the cause for extraesophageal symptoms. However, research
shows conflicting evidence of utility of empiric
acid suppression for these symptoms and an objective test is necessary.
The ambulatory impedance/pH monitoring performed on or off therapy is the best test for studying the gastro-esophageal reflux but can be misleading when the pH is measured in the pharynx.
In addition, up to now is unexplained why in some
patients the reflux reach the proximal esophagus.
Our aim is to study in this patients the esophageal
motility with a new manometric system with 36
pressure sensors that allows to perform an high
resolution manometry.
In addition we study the proximal reflux with a new
pH catheter for the detection of oropharyngeal
acid reflux. The Restech pH catheter uses a nasopharyngeal catheter to measure the pH in either
liquid or aerosolized droplets. The goal of the
study is to understand the physiopathology of the
gastroesophageal-laryngopharyngeal reflux.
Sandro Passaretti
165
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Introduction by the Directors
DRI
Diabetes Research Institute
Type 1 diabetes is a disease resulting from the inability to produce insulin, a hormone essential to regulate glucose and the entire metabolism. The cause of insulin deficiency is the destruction of insulin producing β cells located within the islets of pancreas by the immune system. This process is known as
autoimmune disease and the cause is still unknown. Type 1 diabetes, if left untreated, represents a potentially lethal disease.
Type 1 diabetes is predominantly diagnosed in children and young adults and requires life long multiple
daily injections of insulin and blood glucose monitoring by way of finger pricks for survival and control. This
constant burden greatly affects the quality of life of both patients and family members. Moreover, despite
major and constant advancements of insulin therapy and glucose monitoring, the normalization of blood
glucose over the 24 hour period is not an easy goal to achieve and maintain.
In Europe, the number of new cases is currently two to four times more than in the 1950s. In mainland
Italy, the incidence of type 1 diabetes is 6 to 10 cases per 100.000 inhabitants per year in the 0-14 age
group, whilst in Sardinia the incidence is four times higher. This means that in Italy 4 children or adolescent develop diabetes every day.
At present, there is neither a cure nor prevention for type 1 diabetes.
At San Raffaele research in diabetes and related topics has been consistent and innovative over the
years.
With the objective of reinforcing and expanding the commitment on diabetes research, in 2007 a specialized Research Institute entirely devoted to type 1 diabetes, denominated Diabetes Research Institute
(DRI), was established. Formally incorporated within the Division of Immunology, the DRI is an independent Research Institute
The overall objective of DRI is to prevent and cure T1D. To achieve this objective, two specific programs
are pursued, both of which take advantage of patients and animal models:
1) Prediction and prevention of T1D: this program aims to define mechanisms of induction and perpetuation of autoimmunity and to develop strategies for halting/reverting the progression to T1D.
2) β cell replacement and cell therapy in T1D: this program pursues novel strategies promoting immune
tolerance and islet-regeneration to prolong the survival of native and/or transplanted β cells.
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Research Units, DRI
Experimental diabetes
Role of innate immune cells in the pathogenesis of autoimmune type
1diabetes
The pathogenesis of autoimmune diseases such
as Type 1 Diabetes (T1D) is regulated by genetic
and environmental factors. Those factors act
through modulation of innate immune cell subsets
that are crucial for the immune system’s decision
to initiate autoimmunity or tolerate self-antigens.
Our research is focused on studying the mechanisms through which environmental factors affect
the pathogenesis of autoimmune T1D. Specifically, we aim at investigating how environmental factors modulate autoimmunity by acting on three innate immune cell subsets that play important immune regulatory function such as dendritic cells
(DCs), natural killer T cells (iNKT cells) and mast
cells (MCs). We recently demonstrated that intestinal DCs of T1D patients are defective in their
tolerogenic function and fail to induce peripheral
differentiation of regulatory FoxP3+ T cells. We
are now investigating in human T1D patients as
well as in pre-clinical models of T1D, how alteration of the gut microbiota induced by diet modifications and gluten-induced inflammation, affect
Teff/Treg cell ratio by modulating the tolerogenic
potential of intestinal DCs. iNKT cells represent an
important innate immune cell subsets that play
modulatory function in T1D. We recently demonstrated that regulatory iNKT cells contribute to
maintenance of immune tolerance through the induction of tolerogenic DCs and in the past year
we performed experiments with reporter mice
(iNKT cells purified from Ds-Red mice and injected into CD11cCreXRosa26:EYFP) to analyze by
confocal microscopy and 2P intravital microscopy
the in vivo dynamics of the iNKT-DC interaction.
MCs represent the third innate immune cell subset that we are currently studying to assess its
role in T1D pathogenesis. By using a conditional
MC deficient murine model (mcpt5-Cre-iDTR
mice) backcrossed into the NOD background we
have demonstrated that MC are actively recruited
at the site of autoimmune inflammation, i.e., the
pancreatic islets of diabetic NOD mice, fail to acquire a tolerogenic IL-10-secreting phenotype upon Treg cell- modulation and contribute to T1D
pathogenesis by secreting IL-6 and favoring Th17
cell differentiation (Betto et al. manuscript under
revision).
Marika Falcone
β cell biology Unit
Our project aims to create favorable conditions for
the survival and expansion of β cells under native
conditions and after transplant. Specifically we will:
1) Improve islet transplantation. We started a
phase 3, international, multicenter, randomized,
double-blind trial to evaluate the efficacy and tolerability of an inhibitor of CXCR1/2 receptors after
islet transplantation in patients with T1D
(NCT01817959). We have completed the retrospective observational study aimed at understanding the role of allograft rejection and recurrence of autoimmunity in long-term clinical outcome of islet transplantation, showing that the increase in DSA or autoantibodies after islet transplantation is an important prognostic marker and
its identification has the potential to improve the
outcome of islet cell transplantation. We started a
randomized clinical trial (NCT01722682 ) to evaluate the safety and effectiveness of bone marrow
as a site of islet transplantation. We have completed a pilot study to evaluate the possibility of
using the autologous islet transplantation (IAT) in a
population of patients undergoing pancreatectomy (NCT01702051).
2) Create insulin-producing cells starting from
stem cells. This part of the project investigates the
possibility of isolating stem cells from adult/fetal
tissue and assesses their differentiation potential
toward the insulin-secreting cell phenotype. The
main expected result is a renewable source of
cells that can be used to augment or replace the
transplantable β cell mass. We are actively studying as β cells alternative source: pancreatic
CD133+ cells and reprogrammed fibroblasts.
3) Identify the mechanisms of immunization against
β cell autoantigens. The objective is to determine
the mechanisms of immunization resulting in the
production of pancreatic islet autoimmuniy. Among
the various hypotheses under consideration, we
are currently evaluating the role of the human influenza virus in the processes of development of
diabetes mellitus type 1.
Lorenzo Piemonti
167
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Research Units, DRI
Figure 27. Human pancreatic
islet (brown:insulin staining).
Immune-mediated diseases Unit: from pathogenesis to
treatment
Aims: Ultimate goal of our group is to better understand immune-mediated diseases (i.e., autoimmune type 1 diabetes (T1D) and rejection after transplantation) and to define new approaches
for their prevention and/or cure. Specifically we
aim at: a) characterize the immune responses occurring in the target organ of T1D patients; b) dissect the immunological players in charge of T1D
development; c) understand the immunological
functions of autoimmunity-predisposing genes; d)
explore the mechanisms of transplant tolerance
and e) perform clinical trials with regulatory lymphocytes to re/establish immune tolerance.
Achievements: a) Pancreatic lymph nodes were
collected from patients with T1D. The genomic
and miRNA profiles of T regulatory (Treg) and effector cells have been delineated. miRNA-specificaly expressed only in Tregs isolated from PLN of
patients with T1D and not in their peripheral blood
or in healthy controls have been found and represent an interesting therapeutic target. b) Neutrophils are reduced in individuals at risk of developing T1D and at onset and are localized in their
pancreas. c) PTPN22 is a protein tyrosine phos-
phatase expressed by the majority of the immune
cells and polymorphisms in PTPN22 are associated with autoimmunity. A novel role for PTPN22 in
mediating transplant tolerance is under active investigation. d) We previously developed a mouse
model of allogeneic transplantation in which a
specific immunomodulatory treatment leads to
transplant tolerance through both Foxp3+ Treg
and Tr1 cells. We have now showed that these
Treg cells exert their regulatory function at different
time points after transplantation and from different
sites. e) A clinical trial with donor specific T regulatory type 1 (Tr1) cells is under development for
preventing allograft rejection after kidney transplantation (THE ONE study).
Conclusions: a) A specific genomic and miRNA
signature is present in Treg cells; b) the innate immunity is involved in the pathogenesis of T1D; c)
a previously unreported role for PTPN22 in transplant tolerance is becoming evident; d) a novel relationships between Treg-cell subsets after transplantation is now clear; and e) Tr1 cells are going
to be used in vivo after transplantation in patients.
Manuela Battaglia
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Clinical Research Units, DRI
Prevention in Type 1 diabetes Unit
This line of investigation is pursued within TrialNet,
an international consortium aiming at the prevention or delay of type 1 diabetes. TrialNet is a NIHsupported network of clinical centers, investigators
and core support facilities in the US, Canada,
United Kingdom, Italy, Finland and Australia. In
2002, with the support of the Juvenile Diabetes
Research Foundation (JDRF) a TrialNet Clinical
Center was established at San Raffaele. TrialNet
researchers are working to better understand the
natural history of the disease, identify persons at
risk, and evaluate novel therapies. The fundamental goal of TrialNet is to interdict the T1D disease
process by immune modulation and/or enhancement of β cell proliferation and regeneration. Studies currently ongoing at the San Raffaele TrialNet
Center include: the “Pathway to Prevention Study”,
investigating the natural history of development of
type 1 diabetes and the identification of individuals
at risk; and the “oral insulin trial” for the prevention
of diabetes in relatives at risk. Based on the same
JDRF-funded infrastructure, other clinical trials, in
addition to those performed within TrialNet, are excepted to be performed in the next future in new
onset type 1 diabetes.
Emanuele Bosi
Epidemiology & data management
The mission of the Epidemiology and Data Management Core is to provide methodological support to investigator-initiated clinical research and
translational research projects within the Department of Immunology, Transplantation and Infectious Diseases (including the Diabetes Research
Institute and the Islet Transplant Program). In the
past year the Epidemiology and Data Management Core has been providing support to the following major projects:
• Islet autotransplantation: a randomized multicenter clinical trial to assess whether total pancreatectomy with islet autotransplantation is a
superior alternative to pancreaticoduodenectomy in patients at very high-risk of complications
of the pancreatic anastomosis (soft pancreas
and pancreatic duct diameter
• Self-monitoring of blood glucose in Type 2 diabetes: after publishing the main results of the
PRISMA Study, we are working on additional
analysis on the effect of self-monitoring of capillary glucose on the prescription of diabetes
medication, post-prandial glucose control, and
impact on quality of life and locus of control.
• Diabetes & pregnancy: our clinical research
projects in diabetes and pregnancy include observational studies on the fetal and maternal
outcomes of pregnacies complicated by gestational diabetes in first generation immigrants, incidence of diabetes or impaired glucose tolerance post-partum in women with a history of
gestational diabetes, transition from the twostep to the single step strategy for the screening
of gestational diabetes.
The Epidemiology and Data Management Core is
also conducting a study on the screening practice
for the screening of gestational diabetes in the
population of the Lombardy region. Current
screening practice and compliance to screening
guidelines has never been documented at a population-based level. In collaboration with the Department of Biostatistics of the University of Milano Bicocca and the Unit of Maternal and Fetal
Health we are analyzing the regional Health Care
System archives, including the Certificate of Delivery Care (CEDAP) archive to document the
screening practice for gestational diabetes in over
360.000 pregnancies in the Lombardy Region in
the period 2007-2010.
Marina Scavini
Islet transplantation
The Clinical Islet Transplantation Program activity
has continued the project of developing translational clinical trials. The close interaction between
Clinical Unit and β Cell Biology Unit is the dominant trait of this program.
On going experimental protocols:
• Phase 2 single center, randomized open study:
bone marrow versus liver as site for islet transplantation in patients with type 1 diabetes: pilot
study to evaluate efficacy. 3 patients received
islet into bone marrow; 2 patients received islet
into the liver as control.
• A phase 3, multicenter, randomized, doubleblind, parallel assignment study to assess the
169
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Clinical Research Units, DRI
efficacy and safety of reparixin in pancreatic islet
transplantation. 8 patients were enrolled; 6 patients received completed transplant .
Previous experimental protocols:
The patients recruitment of 2 pilot studies that had
been started up in previous years was completed; the follow-up was ongoing:
• Intra bone marrow islet infusion in patients not
eligible for islet infusion in the liver
• A phase 2 multicenter, randomized, open label,
parallel assignment, pilot study to assess the efficacy and safety of reparixin following a singleinfusion of islet in patients with type 1 diabetes
mellitus: 9 patients were included at our center,
they received islet transplant and the infusion of
reparixin.
The follow-up of patients who received islet allotransplant in previous clinical trials and islet autotransplant protocols has been continued. Followup of clinical trials:
Islet Allotransplant
• Edmonton protocol
• Pre transplant rapamycin treatment associated to
the Edmonton protocol
• Calcineurin inhibitor free immunosuppression
protocol
• Effect of islet transplant alone on long-term diabetes complications (early retinopathy,neuropathy,
carotid artery disease)
• Prospective study of kidney function and incidence
of cancer in islet transplant alone
• Islet and kidney transplant.
Islet Autotransplant
• Total pancreatectomy with islet autotransplant as
a superior alternative to pancreatoduodenectomy
in patients at very high-risk of complications of the
pancreatic anastomosis: a single-center prospected randomised clinical trial;
• Islet autotransplant in patients who underwent total or partial pancreatectomy.
Paola Maffi
Childhood diabetes
The Childhood Diabetes Unit is mainly focused on
clinical research aimed to prevent and cure type 1
diabetes in children and adolescents.
The Unit presently represents one of the biggest
centers for the study of type 1 diabetes in Italy as
it follows more than 900 diabetic children, including 300 patients treated with intensive insulin therapy. More than 70 new cases of diabetes are diagnosed every year.
The Unit actively collaborates with other research
groups both inside and outside the San Raffaele
Scientific Institute, in particular:
1. collaboration with the Units of Dr. Battaglia and
Dr. Piemonti (Diabetes Research Institute, San
Raffaele Scientific Institute) aimed to study
newly diagnosed children in order to better understand the immunological and virological
bases of type 1 diabetes. Along with the same
research groups we are also involved in a
study aimed to clarify whether patients with different β cell residual secretion also differ for immunological markers. On this regard we submitted a grant application to the Juvenile Diabetes Research Foundation aimed to study
long term residual β cell secretion in type 1 diabetic patients.
2. we have a collaboration with Prof. Lorenzi
(Schepen’s Eye Research Institute, Harvard
Medical School, Boston, MA, USA) and Dr.
Zerbini (Diabetes Research Institute, San Raf-
faele Scientific Institute) to understand if biomarkers for microvascular complications are
detectable in children with diabetes. We submitted a grant application to the National Institute of Health (NIH) to study the progression of
diabetic complications taking advantage of a
novel, non-invasive approach.
3. The Unit, as a member of an active research
network (SIEDP), has been previously involved
in multicenter trials recently published (VIPKIDS, SHIPD), and it is now part of a large
study aimed to investigate diabetic chetoacidosis at diagnosis of type 1 diabetes and to verify
insulin pump malfunctioning in children treated
with intensive insulin therapy.
4. The Unit is an active member of the Italian
Group of Diabetes Technology and last year
we performed a study on intensive insulin therapy in diabetic patients in Italy (IMITA study),
that will be published soon.
5. We have an ongoing collaboration with Prof.
Barbetti (Rome) and Prof. Iafusco (Naples) to
study children with rare genetic cause of diabetes.
6. We are part of the writing team of the Società
italiana di endocrinologia pediatrica (SIEDP),
our aim is to define the guidelines for insulin
therapy and chetoacidosis treatment in children with type 1 diabetes.
Riccardo Bonfanti
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Selected publications
Canducci, F; Ceresola, ER; Saita, D; Castagna, A; Gianotti, N; Underwood, M; Burioni, R; Lazzarin, A; Clementi, M. In vitro phenotypes to elvitegravir and dolutegravir in primary macrophages and
lymphocytes of clonal recombinant viral variants selected in patients failing raltegravir. J. Antimicrob.
Chemother.: 2013; 68(11): 2525-2532 - Article
IF 2012: 5,338
Capua, I; Mercalli, A; Pizzuto, MS; Romero-Tejeda, A; Kasloff, S; De Battisti, C; Bonfante, F; Patrono,
LV; Vicenzi, E; Zappulli, V; Lampasona, V; Stefani, A; Doglioni, C; Terregino, C; Cattoli, G; Piemonti,
L. Influenza A viruses grow in human pancreatic cells and cause pancreatitis and diabetes in an animal model. J. Virol.: 2013; 87(1): 597-610 - Article
IF 2012: 5,076
Cassetta, L; Kajaste-Rudnitski, A; Coradin, T; Saba, E; Della Chiara, G; Barbagallo, M;
Graziano, F; Alfano, M; Cassol, E; Vicenzi, E; Poli, G. M1 polarization of human monocyte-derived
macrophages restricts pre and postintegration steps of HIV-1 replication. AIDS: 2013; 27(12): 18471856 - Article
IF 2012: 6,407
Cassol, E; Cassetta, L; Rizzi, C; Gabuzda, D; Alfano, M and Poli, G. Dendritic Cell-Specific ICAM3 Grabbing Nonintegrin mediates HIV-1 Infection of and Transmission by M2a-Polarized Macrophages
In Vitro. AIDS: 2013; 27(5): 707-716 - Article
IF 2012: 6,407
Castagnaro, L; Lenti, E; Maruzzelli, S; Spinardi, L; Migliori, E; Farinello, D; Sitia, G; Harrelson, Z;
Evans, SM; Guidotti, LG; Harvey, RP; Brendolan, A. Nkx2-5+islet1+ mesenchymal precursors generate distinct spleen stromal cell subsets and participate in restoring stromal network integrity. Immunity: 2013; 38(4): 782-791 - Article
IF 2012: 19,795
Cavarelli, M; Foglieni, C; Rescigno, M; Scarlatti, G. R5 HIV-1 envelope attracts dendritic cells to
cross the human intestinal epithelium and sample luminal virions via engagement of the CCR5.
EMBO Mol. Med.: 2013; 5(5): 776-794 - Article
IF 2012: 7,795
Cieri, N; Camisa, B; Cocchiarella, F; Forcato, M; Oliveira, G; Provasi, E; Bondanza, A; Bordignon,
C; Peccatori, J; Ciceri, F; Lupo-Stanghellini, MT; Mavilio, F; Mondino, A; Bicciato, S; Recchia, A;
Bonini, C. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood: 2013; 121(4): 573-584 - Article
IF 2012: 9,060
Ghezzi, S; Galli, L; Kajaste-Rudnitski, A; Turrini, F; Marelli, S; Toniolo, D; Casoli, C; Riva, A; Poli,
G; Castagna, A; Vicenzi, E. Identification of TRIM22 single nucleotide polymorphisms associated with
loss of inhibition of HIV-1 transcription and advanced HIV-1 disease. AIDS: 2013; 27(15): 2335-2344
- Article
IF 2012: 6,407
Giannese, F; Berg, M; Van Der Veken, P; Castagna, V; Tornaghi, P; Augustyns, K; Degano, M.
Structures of purine nucleosidase from Trypanosoma brucei bound to isozyme-specific trypanocidals
and a novel metalorganic inhibitor. Acta Crystallogr. Sect. D Biol. Crystallogr.: 2013; 69(8): 1553-1566
- Article
IF 2012: 14,103
Hess Michelini, R and Manzo, T; Sturmheit, T; Basso, V; Rocchi, M; Freschi, M; Listopad, J;
Blankenstein, T; Bellone, M and Mondino, A. Vaccine-instructed intratumoral IFN-g enables regression
of autochthonous mouse prostate cancer in allogeneic T-cell transplantation. Cancer Res.: 2013;
73(15): 4641-4652 - Article
IF 2012: 8,650
Maffi, P and Balzano, G; Ponzoni, M; Nano, R; Sordi, V; Melzi, R; Mercalli, A; Scavini, M; Esposito, A; Peccatori, J; Cantarelli, E; Messina, C; Bernardi, M; Del Maschio, A; Staudacher, C;
Doglioni, C; Ciceri, F; Secchi, A; Piemonti, L. Autologous Pancreatic Islet Transplantation in Human
Bone Marrow. Diabetes: 2013; 62(10): 3523-3531 - Article
IF 2012: 7,895
Napolitano, A; Pittoni, P; Beaudoin, L; Lehuen, A; Voehringer, D; MacDonald, HR; Dellabona, P;
Casorati, G. Functional education of invariant NKT cells by dendritic cell tuning of SHP-1. J. Immunol.:
171
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Selected publications, DRI
2013; 190(7): 3299-3308 - Article
IF 2012: 5,520
Pensieroso, S; Galli, L; Nozza, S; Ruffin, N; Castagna, A; Tambussi, G; Hejdeman, B; Misciagna,
D; Riva, A; Malnati, M; Chiodi, F and Scarlatti, G. B-cell subset alterations and correlated factors in
HIV-1 infection. AIDS: 2013; 27(8): 1209-1217 - Article
IF 2012: 6,407
Ricupito, A; Grioni, M; Calcinotto, A; Hess Michelini, R; Longhi, R; Mondino, A; Bellone, M.
Booster vaccinations against cancer are critical in prophylactic but detrimental in therapeutic settings.
Cancer Res.: 2013; 73(12): 3545-3554 - Article
IF 2012: 8,650
Tonti, E; Jimenez de Oya, N; Galliverti, G; Moseman, E; Di Lucia, P; Amabile, A; Sammicheli,
S; De Giovanni, M; Sironi, L; Chevrier, N; Sitia, G; Gennari, L; Guidotti, LG; Von Andrian, U; Iannacone, M. Bisphosphonates Target B Cells to Enhance Humoral Immune Responses. Cell Rep.:
2013; 5(2): 323-330 - Article
IF 2012: Indexed by JCR 2012
Selected publications, DRI
Balzano, G; Maffi, P; Nano, R; Zerbi, A; Venturini, M; Melzi, R; Mercalli, A; Magistretti, P; Scavini, M; Castoldi, R; Carvello, M; Braga, M; Del Maschio, A; Secchi, A; Staudacher, C; Piemonti,
L. Extending indications for islet autotransplantation in pancreatic surgery. Ann. Surg.: 2013; 258(2):
210-218 - Article
IF 2012: 6,329
Gagliani, N; Jofra, T; Valle, A; Stabilini, A; Morsiani, C; Gregori, S; Deng, S; Rothstein, DM; Atkinson, M; Kamanaka, M; Flavell, RA; Roncarolo, MG; Battaglia, M. Transplant tolerance to pancreatic islets is initiated in the graft and sustained in the spleen. Am. J. Transplant.: 2013; 13(8): 19631975 - Article
IF 2012: 6,192
Maffi, P and Balzano, G; Ponzoni, M; Nano, R; Sordi, V; Melzi, R; Mercalli, A; Scavini, M; Esposito, A; Peccatori, J; Cantarelli, E; Messina, C; Bernardi, M; Del Maschio, A; Staudacher, C;
Doglioni, C; Ciceri, F; Secchi, A; Piemonti, L. Autologous Pancreatic Islet Transplantation in Human
Bone Marrow. Diabetes: 2013; 62(10): 3523-3531 - Article
IF 2012: 7,895
Piemonti, L; Everly, MJ; Maffi, P; Scavini, M; Poli, F; Nano, R; Cardillo, M; Melzi, R; Mercalli, A;
Sordi, V; Lampasona, V; De Arias, AE; Scalamogna, M; Bosi, E; Bonifacio, E and Secchi; A and
Terasaki; PI. Alloantibody and autoantibody monitoring predicts islet transplantation outcome in human
type 1 diabetes. Diabetes: 2013; 62(5): 1656-1664 - Article
IF 2012: 7,895
Valle, A and Giamporcaro, GM and Scavini, M; Stabilini, A; Grogan, P; Bianconi, E; Sebastiani,
G; Masini, M; Maugeri, N; Porretti, L; Bonfanti, R; Meschi, F; De Pellegrin, M; Lesma, A; Rossini,
S; Piemonti, L; Marchetti, P; Dotta, F; Bosi, E; Battaglia, M. Reduction of circulating neutrophils precedes and accompanies type 1 diabetes. Diabetes: 2013; 62(6): 2072-2077 - Article
IF 2012: 7,895
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Protein engineering and therapeutics
AIDS immunopathogenesis Unit
173
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Cellular immunology Unit
Emerging bacterial pathogens Unit
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Experimental immunology Unit
Lymphocyte activation Unit
175
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Viral evolution and transmission Unit
Viral pathogens and biosafety Unit
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Management and antiretroviral treatment of HIV infection
Neurovirology
177
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Research Units
Study and treatment of hepatotropic viruses related diseases
Clinical immunopathology and advanced medical therapeutics Unit
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Clinical transplant Unit
Experimental diabetes
179
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
β cell biology Unit
Immune-mediated diseases Unit: from pathogenesis to treatment
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Infection and cystic fibrosis
181
DIVISION
OF
GENETICS AND
CELL BIOLOGY
Director:
Roberto Sitia*
Associate Director:
Marco E. Bianchi*
Research Units
Protein transport and secretion Unit –––––––––––––––––––––––––––––––––––––––––––––––––––– 187
HEAD OF UNIT: Roberto Sitia*
RESEARCHER: Tiziana Anelli
POST-DOCTORAL FELLOWS: Iria Medraño Fernandez**, Maria Francesca Mossuto, Edgar
Yoboue
PHD STUDENTS: Milena Bertolotti**, Sara Sannino
FELLOW: Stefano Bestetti
TECHNICIAN: Claudio Fagioli
Age related diseases ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 188
GROUP LEADER: Simone Cenci
POST-DOCTORAL FELLOWS: Nicola Napoli, Laura Oliva
PHD STUDENT: Enrico Milan**
FELLOW: Ugo Orfanelli
TECHNICIANS: Elisabetta Mariani, Massimo Resnati
Molecular immunology –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 188
GROUP LEADER: Antonio Siccardi
RESEARCHER: Maddalena Panigada
POST-DOCTORAL FELLOWS: Francesca Bosè, Francesco Gubinelli
PHD STUDENTS: Andrea Barbieri, Marta Recagni
TECHNICIAN: Elisa Soprana
Chromatin dynamics Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 189
HEAD OF UNIT: Marco E. Bianchi*
POST-DOCTORAL FELLOWS: Elena Gatti, Michelle Monasky**, Emilie Venereau
FELLOW: Giovanni Pietrogrande
TECHNICIAN: Francesco De Marchis
183
DIVISION OF GENETICS AND CELL BIOLOGY
Research Units
In vivo Chromatin and transcription –––––––––––––––––––––––––––––––––––––––––––––– 190
GROUP LEADER: Alessandra Agresti
POST-DOCTORAL FELLOW: Samuel Zambrano
PHD STUDENT: Ilario De Toma **
Molecular dynamics of the nucleus ––––––––––––––––––––––––––––––––––––––––––––––– 191
RESEARCHER: Massimo Crippa
Biology of myelin Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 191
SCIENTIFIC ADVISOR: Lawrence Wrabetz
HEAD OF UNIT: Roberto Sitia*
POST-DOCTORAL FELLOWS: Maurizio D’Antonio, Nicolò Musner, Cristina Scapin
PHD STUDENTS: Domenica Vizzuso**, Vera Giulia Volpi**
TECHNICIANS: Cinzia Ferri, Emanuela Pettinato
Biomolecular mass spectrometry Unit –––––––––––––––––––––––––––––––––––––––––––––––––– 192
HEAD OF UNIT: Marco E. Bianchi* (ad interim)
POST-DOCTORAL FELLOW: Umberto Restuccia
PHD STUDENT: Vittoria Matafora
FELLOW: Simone Tamburri
TECHNICIAN: Angela Cattaneo
European Institute for Research in Cystic Fibrosis (IERFC) –––––––––––––––––––––––– 192
HEAD OF UNIT: Luigi Maiuri
POST-DOCTORAL FELLOWS: Emanuela Bruscia (until March 2013), Daniela De Stefano,
Speranza Esposito, Konstantina Kyritsi, Valeria Villella
FELLOWS: Eleonora Ferrari, Romina Monzani
Genetics of common disorders Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––– 193
HEAD OF UNIT: Daniela Toniolo
PHD STUDENT: Michela Traglia
FELLOWS: Caterina Maria Barbieri, Corrado Masciullo
TECHNICIAN: Cinzia Sala
Intracellular signaling pathways Unit ––––––––––––––––––––––––––––––––––––––––––––––––––– 193
GROUP LEADER: Eelco Van Anken, Armenise-Harvard Career Development Award
POST-DOCTORAL FELLOWS: Anush Bakunts, Andrea Orsi
PHD STUDENT: Milena Vitale
Molecular basis of polycystic kidney disease Unit ––––––––––––––––––––––––––––––––––– 194
HEAD OF UNIT: Alessandra Boletta*
POST-DOCTORAL FELLOWS: Maddalena Castelli, Isaline Rowe
PHD STUDENT: Monika Pema**
FELLOWS: Chiara De Pascalis, Luca Drusian
TECHNICIANS: Marco Chiaravalli, Gianfranco Distefano
NeuroGlia Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 194
SCIENTIFIC ADVISOR: Maria Laura Feltri
HEAD OF UNIT: Roberto Sitia*
RESEARCHER: Daniela Talarico
POST-DOCTORAL FELLOW: Ernesto Pavoni
PHD STUDENTS: Cristina Colombelli, Monica Ghidinelli**, Marilena Palmisano**
FELLOW: Alberto Merli
TECHNICIAN: Desirée Zambroni
DIVISION OF GENETICS AND CELL BIOLOGY
Research Units/Clinical Research Units
Regulation of iron metabolism Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––– 196
HEAD OF UNIT: Clara Camaschella*
POST-DOCTORAL FELLOWS: Alessandro Campanella, Antonella Nai**, Alessia Pagani,
Laura Silvestri
PHD STUDENT: Marco Rausa
Molecular genetics of renal disorders Unit (Dulbecco Telethon Institute) –––––– 196
GROUP LEADER: Luca Rampoldi
POST-DOCTORAL FELLOWS: Céline Schaeffer, Matteo Trudu
PHD STUDENT: Martina Brunati**
FELLOW: Anna Creatore
TECHNICIAN: Elena Pasqualetto
Clinical Research Units
Dento-facial histopathology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 197
HEAD OF UNIT: Enrico Gherlone*
PHYSICIANS: Enrico Agliardi, Paolo Capparé, Giuseppe Cardaropoli, Roberto Crespi, Maria
Gabriella Grusovin, Alessandra Lucchese*, Simona Tecco, Raffaele Vinci
Genomics of renal diseases and hypertension Unit –––––––––––––––––––––––––––––––––– 197
HEAD OF UNIT: Paolo Manunta*
CLINICAL GROUP LEADER: Donatella Spotti
RESEARCHER: Laura Zagato
PHYSICIANS: Teresa Arcidiacono, Chiara Lanzani, Maria Teresa Sciarrone Alibrandi, Marco
Simonini, Giuseppe Vezzoli
CONSULTANTS: Giuseppe Bianchi*, Mara Ferrandi, Isabella Molinari
RESIDENTS: Guido Gatti**, Lino Merlino**, Marina Nuzzo**, Simona Pozzoli**, Stefano
Tentori**, Francesco Trevisani**
FELLOWS: Lorena Citterio, Simona Delli Carpini, Elisabetta Messaggio
TECHNICIAN: Nunzia Casamassima
RESEARCH NURSES: Elena Brioni, Marie Jankaricova
Reproductive sciences Lab –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 198
HEAD OF UNIT: Massimo Candiani*
CLINICAL GROUP LEADER: Paola Panina
RESEARCHERS: Enrico Papaleo, Paola Viganò
POST-DOCTORAL FELLOWS: Alessandra Mugione**, Ana Maria Sanchez**
FELLOWS: Laura Corti, Luca Pagliardini
Tissue engineering and biomaterials –––––––––––––––––––––––––––––––––––––––––––––––––––– 199
HEAD OF UNIT: Gianfranco Fraschini
CLINICAL GROUP LEADER: Giuseppe M. Peretti
PHYSICIAN: Marco Domenicucci
POST-DOCTORAL FELLOWS: Elena Arrigoni, Elisa Benasciutti, Daniela Deponti, Celeste
Scotti
RESIDENTS: Marco Agnoletto, Marco Melato
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
185
DIVISION OF GENETICS AND CELL BIOLOGY
Introduction by the Directors
Mission and vision - The Division of Genetics and Cell Biology (DGCB) aims at the mechanistic comprehension of biological and pathological phenomena, to acquire basic knowledge and provide fellow clinicians with novel concepts, tools and protocols. Understanding physiology and pathology in cellular and
molecular terms is fundamental to cure disease and create novel biotechnologies. The creation of new
tools impacts directly on diagnostics. Scientific training and outreach are also DGCB priorities.
Organization - DGCB consists of 15 basic, 4 clinical research groups and 2 facilities, totaling about 150
staff. Scientists are encouraged to foster synergies and engage in competitive projects. Areas of particular strength include the pathophysiology of stress and inflammatory responses, kidney and iron metabolism, the genetics of complex disorders, chromatin dynamics and epigenetics, cell polarity. Our staff are
active in numerous Research Programs and Facilities.
Goals - DGCB fosters curiosity-driven research projects that aim at understanding the molecular and cellular bases of biological phenomena and human diseases for the benefit of knowledge, technology and
patients. The iterative process of translation is a key asset for DGCB, which aims providing clinical sciences with novel concepts and protocols and robust cell or animal models for their testing. As important
is reverse translation, where detailed patient analyses can unravel physiological mechanisms. Research
on genetic diseases is an example: identifying mutational hotspots in patients, for instance, sheds light
on basic functions and allows for identification of novel bio-markers and therapeutic targets.
Another important aim is to develop strong, reliable and quantitative and high-throughput assays. To this
end we work in close collaboration with institutional Centers and Facilities to develop state-of-the-art
technological platforms. The Proteomic service and the Center for conditional mutagenesis represent
successful examples of our strategy: they are at the technological forefront and are serving a vast number of intramural and external scientists and clinicians.
Achievements - 2013 has been a particularly successful year for DGCB scientists. A number of projects
have come to fruition as high-impact papers appearing in top journals. The reader is referred to reports
of the single laboratories for details on these accomplishments. Suffice here to recall the demonstration
of the essential role of autophagy in plasma cell differentiation and long term antibody production; the unexpected finding that uromodulin levels impact blood pressure, besides causing kidney diseases when
mutated; the further mechanistic characterization of the iron metabolism circuitry in human cells; the characterization of a novel, pH-dependent mechanism of protein quality control; the definition of new roles for
redox control in inflammation and tyrosine kinase signaling; and, the observation that defective glucose
metabolism is intimately involved in the pathobiology of polycystic kidney disease, paving the way for
novel therapeutic strategies with existing drugs.
The Core Facility for Conditional Mutagenesis generated 7 gene-targeted and 4 transgenic new lines, and
cryopreserved/rederived over 40 lines for intra- and extra-mural scientists. The Protein Microsequencing
Facility increased the number of internal (>15) and external users (≥20). Having acquired new instruments, ProMiFa can now further extend its portfolio. DGCB staff contributed significantly to developing
metabolomics and imaging protocols.
Training Opportunities - DGCB hosts many undergraduate students for their experimental theses and attractive PhD and PostDoctoral training programs, offering positions on competitive bases. Many scientists visited DGCB laboratories for sabbatical or training periods. DGCB organised numerous well-attended
and lively seminars, delivered internal and external invitees.
DIVISION OF GENETICS AND CELL BIOLOGY
Research Units
Protein transport and secretion Unit
Proteostasis, redoxtasis and signal integration in the early secretory compartment
A fundamental question in biology is how cells coordinate the size and activity of the different compartments. Our lab investigates the integration of
signalling, protein quality control and sorting at the
endoplasmic reticulum (ER)-Golgi interface.
We discovered that ERp44 is a master regulator in
this hub, regulating Ca2+ signalling, redox homeostasis (redoxtasis) and proteostasis. ERp44 acts
as a pH-dependent chaperone that cycles within
the early secretory compartment (ESC) and interacts with other key regulatory molecules (Ero1α,
peroxiredoxin 4, IP3R1, KDEL receptors) to guarantee membrane homeostasis, transport efficiency
and fidelity of the secretory proteome (Anelli et al.,
2012; Vavassori et al. 2013; Kakihana et al., 2013;
Benham et al., 2013; Wang et al., 2014; MedrañoFernandez et al., 2014).
We developed powerful models of ER storage
disorders and novel technologies to investigate
what controls protein aggregation in ESC (Anelli
and Sitia, 2010), and design suitable treatments.
We confirmed that the degradative load vs. capacity ratio dictates sensitivity to bortezomib, a
drug currently used against myeloma and other
plasma cell dyscrasias and showed how au-
tophagy and iron metabolism impact ESC proteostasis (Cenci, van Anken and Sitia 2011;
Campanella et al., 2013; Pengo et al. 2013). We
developed metabolomic platforms (Garcia-Manteiga et al., 2011) to identify markers of myeloma
progression (Fontana et al., submitted).
We demonstrated that aquaporin 8 mediates
H2O2 transport across the endoplasmic reyiculum and plasma-membranes, allowing entry of
H2O2 generated by NOXes to amplify tyrosine kinase signal transduction (Bertolotti et al., 2013).
Modulating redox signaling may open novel possibilities of intervention to control inflammation,
cancer cell migration and apoptosis.
Our findings open the way to develop combinatorial treatments – i.e. targeting autophagy or redoxtasis - for overcoming drug resistance in the treatment of multiple myeloma. Deciphering the connections between ESC proteostasis, redoxtasis
and signaling should identify novel targets for manipulating (mal)adaptive stress responses (Masciarelli et al., 2010; Rubartelli and Sitia, 2009a, b),
and treating ER storage and conformational diseases.
Roberto Sitia
Figure 28. IgM subunits and other client proteins (in dark blue) bind to ERGIC53 at the neutral pH of the endoplasmic
reticulum (>7). Oligomerization takes place as clients proceed to the cisGolgi. Also ERp44 binds to ERGIC53 (Anelli et
al., 2007, EMBO J; Cortini and Sitia, 2010, Traffic). As the pH drops below 6.6 in the cisGolgi, ERGIC53 releases
cargo glycoproteins while ERp44 and KDEL receptors are activated (red to orange shift). Movements of the C-tail of
ERp44 expose the substrate-binding site (thick white arrow) and RDEL motif (yellow anchor), allowing capture of the
clients and their retrieval to the ER by KDEL-R (Vavassori et al., 2013, Mol. Cell; Sannino et al., submitted).
187
DIVISION OF GENETICS AND CELL BIOLOGY
Research Units
Age related diseases
New insights in plasma cell ontogenesis
The CenciLab studies the biology of normal plasma cells (PC), terminally differentiated effectors of
Ab responses, and their malignant degeneration,
multiple myeloma (MM), responsible for 2% of all
cancer deaths. In particular, we are interested in
the role of autophagy, a crucial asset ensuring
proteome plasticity, in PC ontogenesis and
myeloma. Our goal is to identify new prognostic
markers and molecular targets against PC malignancies. Synergic studies on the skeletal microenvironment provide the framework to explore
the vicious relationship of myeloma with the bone
marrow.
Cancer cells rely on protein homeostasis, providing therapeutic targets: proteasome inhibitors (PI),
the prototypical negative proteostasis regulators,
emerged as potent anti-cancer drugs, especially
against MM (Cenci, Semin Hematol 2012; Cenci,
Mol Immunol 2014). We recently contributed to
clarify the bases underlying the exquisite sensitivi-
ty of MM to PI, establishing the concept that high
proteasme workload and limited proteasome capacity are key determinants of PI sensitivity
(Bianchi et al, Blood, 2009; Cenci et al, J Leuk Biol 2012).
In 2013, we disclosed a novel, specific and essential function of autophagy in PC ontogenesis.
In differentiating PCs, autophagy contains the size
of the endoplasmic reticulum, PC differentiation
signals (XBP-1, Blimp-1), and Ab production, to
optimize energy metabolism and sustain Ab responses. Moreover, autophagy is required for the
maintenance of bone marrow memory PCs, the
normal counterpart of MM (Pengo et al, Nat Immunol 2013). This discovery provides a framework for identifying new prognostic markers and
molecular targets against PC malignancies (Pengo & Cenci, Autophagy 2013; Oliva & Cenci,
Front Immunol 2014).
Simone Cenci
Molecular immunology
Adjuvant IgE, headless hemagglutinins, survivin vaccines
1) Endogenous IgE against cancer (with L. Vangelista & A. Brini, Farmacologia, Unimi).
Balb/c mutant KN1, a “high IgE responder” carrying a γ-1/ε gene substitution, shows minimal
growth of subcutaneous tumors and of lung dissemination of i.v. administered tumors. The effect
was shown to be due to immunization by cancer
antigens and anti-tumor IgE-priming of effector
cytotoxic cell, as demonstrated by CD8 depletion
studies. Normal tumor growth is restored in the
double mutant KN1/ Fc-ε RI-KO, indicating that
anti-tumor immunity depends on IgE-driven antigen processing and presentation, in analogy to
the adjuvanticity mechanism previously described
for exogenous IgE.
2) Recombinant headless hemagglutinins as “universal” infuenza vaccines (with E. Vicenzi).
Wide-spectrum neutralizing antibodies directed to
stalk hemagglutinin conformational epitopes are
normal, but very rare, because of the immunodominance of strain-specific epitopes in the
globular head. Headless mutants could overcome
the dominance, but loose the conformation necessary to be exported to the cell surface and fail
to elicit protective responses. Compensatory mu-
tations which allow the surface expression of epitopes reactive with anti-stalk monoclonal antibodies would allow the construction of wide-spectrum vaccines. Their selection from recombinant
mutagenized poxvirus has been so far elusive, but
new strategies employing artificial random mutant
repertoires and stable lentiviral transfectants have
been developed (with E. Montini).
3) Survivin as a “universal” tumor marker (with L.
Piemonti).
Recombinant poxviruses expressing human or
murine survivin have been produced and are currently tested as preventive or curative vaccines in
a number of mouse tumor models, in collaboration
with several groups. Significant protection from
tumor growth in immunized animals has been obtained in a mouse orthotopic model of pancreatic
carcinoma. A study on therapy of murine mesothelioma by FPV-survivin vaccination has been published (with P. Bertino, Hawai’i University). Survivin
vaccines have been included among candidate
tumor vaccines for the innovative Self-Amplifying
RNA vaccination platform (collaboration with D.
Maione, Novartis Research, Siena).
Antonio Siccardi
DIVISION OF GENETICS AND CELL BIOLOGY
Figure 29. Lung tumor dissemination
Chromatin dynamics Unit
HMGB1 as a DAMP (Damage Associated Molecular Pattern)
The state of chromatin determines the identity of
different (but genetically identical) cells in the
same organism. Notably, we discovered in 2002
that a chromatin protein (HMGB1) is also a Damage Associated Molecular Pattern (DAMP) and a
key player in immunity.
HMGB1 is released by dead cells to signal tissue
damage, and is also actively secreted by cells under severe stress, for example by hypoxic cells,or
by activated monocytes/macrophages. HMGB1
contains 3 cysteines and has multiple redox
states, each of which behaves in distinctly different ways: completely reduced HMGB1 forms a
complex with the chemokine SDF-1/CXCL12,
which engages the CXCR4 receptor and recruits
monocytes to the site of tissue damage; HMGB1
containing one disulfide bond between C23 and
C45 interacts with Toll-like receptor 4 (TLR4) and
promotes the synthesis of various pro-inflammatory cytokines and chemokines; sulfone HMGB1
(in which at least one cysteine is completely oxidized to sulfonate) has no activity either as
chemoattractant or proinflammatory signal.
We are currently investigating how the different redox forms of HMGB1 alert the immune system to
tissue damage, trigger inflammation and then direct tissue reconstruction.
We are also investigating a novel concept: that
cancer cells secrete HMGB1 to enlist the help of
the immune system, as if they were a damaged
tissue in need of repair. We have already demonstrated that an anti-HMGB1 monoclonal antibody
developed by us slows mesothelioma growth in a
mouse model.
Our findings provide mechanistic links between
HMGB1 release, acute and chronic inflammation,
and carcinogenesis. We are now developing different agonists or inhibitors of HMGB1 for therapy.
Marco E. Bianchi
189
DIVISION OF GENETICS AND CELL BIOLOGY
Research Units
In vivo Chromatin and transcription
Nucleosome modulation in the cellular response to inflammation and stress
HMGB1 (High Mobility Group Box 1) is a very
abundant and conserved protein that localizes
mainly in the cell nucleus, where it facilitates nuclear transactions (Bianchi & Agresti, 2005). Remarkably, cells lacking HMGB1 from their nuclei
show a 20% decrease in nucleosome content,
possibly because they lack HMGB1-driven DNA
bending activity for nucleosome deposition (Celona
et al,2011). The reduction in nucleosome number
results in a global 30% increase in transcription and
increased susceptibility of DNA to damage.
HMGB1 also has an extracellular signalling function as a Damage Associated Molecular Pattern
(DAMP) molecule (Bianchi, 2007). Necrotic cells
release HMGB1 passively while cells undergoing
severe stress and immune cells stimulated with
LPS or IFN-γ secrete it actively (Bonaldi et al,
2003). Upon stimulation, HMGB1 relocates from
the nucleus to the cytoplasm leaving nuclei partially or totally devoid of HMGB1.
The immune functions of HMGB1 have traditionally been attributed to its actions as a secreted protein. We asked, however, whether the depletion
of HMGB1 from the nuclei of secreting cells might
also play a role in the overall response of inflammatory cells to trauma and stress.
We found that Hmgb1–/– MEFs, inflammation
non-proficient cells, show an inflammatory transcription phenotype and can be considered a
model for cells that have lost HMGB1 from their
nuclei (DeToma et al, 2014, in press).
We then asked whether cells secreting HMGB1
also rearrange their chromatin. We found that unstimulated macrophages lacking HMGB1 show a
molecular phenotype associated to the response
to stress and inflammation. Remarkably, wild type
macrophages that secrete HMGB1 following exposure to LPS and IFN-γ, reduce their histone
content almost as much as macrophages where
HMGB1 has been genetically deleted.
We envisage chromatin rearrangement due to nucleosome loss as an important event in the cellular response to inflammation and stress (Figure 30).
We expect to find similar outcomes upon a variety
of insults where HMGB1 is secreted: infection, ischemia/reperfusion and neuronal hyperexcitation
are likely candidates.
Overall, modulation of nucleosome number may
emerge as a critical event in many physiological
and pathological conditions of clinical interest.
Alessandra Agresti
Figure 30. HMGB1-driven nucleosome depletion facilitates the chemotactic response in M1 macrophages
Macrophages patrolling tissues for enemies express PAMPs receptors (Pathogen Associated Molecular Pattern,
e.g. LPS) and chemokines (Cxcl12) (A, Left). Upon infection, LPS activates the TLR4 receptor on macrophages
membranes., HMGB1 is then secreted eliciting a concomitant loss of histones from the nucleus. When activated,
macrophages unpackage their chromatin in order to access and transcribe the necessary genes. Among the
hundreds of LPS activated genes, those involved in chemotaxis and extravasation are also expressed (A, Right).
Macrophages genetically lacking HMGB1 (B) contain 20% fewer nucleosomes similarly to LPS-activated
macrophages. Remarkably, the transcriptional phenotype overlaps with a subset of the LPS-response containing
chemokines, cytokines and CAMs molecules.
DIVISION OF GENETICS AND CELL BIOLOGY
Molecular dynamics of the nucleus
A syngeneic approach to malignant mesothelioma
Malignant mesotehlioma (MM) is a very aggressive cancer with poor prognosis, because of late
stage diagnosis and resistance to current conventional therapies.
Asbestos-exposed, primary human mesothelial
cells release High Mobility Group Box1 (HMGB1)
protein, a Damage-Associated Molecular Pattern
(DAMP) polypeptide, that establishes an autocrine
circuit making MM cells “addicted” to HMGB1 for
their viability, proliferation and survival. Accordingly, anti-HMGB1 antibodies reduce the growth of
MM xenografts in Severe-Combined ImmunoDeficient (SCID) mice and extend host survival, suggesting that ablation of HMGB1 may be sufficient
to elicit therapeutic activity.
As DAMP, extracellular HMGB1 plays a role in
sterile inflammation, associated with several types
of cancer. HMGB1 acts both as a chemoattractant for leukocyes and as a proinflammatory mediator inducing the release of cytokines and
chemokines by leukocytes and resident immune
cells. Thus a comprehensive approach to the role
of HMGB1 in MM entails a whole-animal system
in which the immune response is fully functional.
We have set up such a system using murine MM
cells (AB1), obtained from tumors induced by asbestos in BALB/c mice.
Intraperitoneal injection of 3 x 104 – 106 AB1
cells in syngeneic BALB/c mice induces the formation of tumors in approximately one week. We
monitor the tumors by ultrasound and PET scans,
providing information on their growth rate, vascularization, expansion in the peritoneal cavity, association with residing organs and metabolism. The
cellular composition of explanted tumors is
analysed by immunohistochemistry and related to
the above observations.
We plan to add optical imaging (IVIS) by using
AB1 cells expressing either the luciferase or the
infraRed Fluorescent Protein gene. Further molecular work will be aimed at understanding which redox form of HMGB1 is responsible for the observed phenotype and through which mechanism
(chemoattraction of leukocytes or proinflammatory
cytochine production). Furthermore, this system
will allow testing a number of molecules as potential therapeutics for MM.
Massimo Crippa
Biology of myelin Unit
Genesis and maintenance of myelin
We have a long-standing interest in myelin, which
permits rapid conduction of impulses and guarantees axonal health in the nervous system. We have
explored the role of axonal signals, adhesion and
transcriptional regulation in myelination. In particular, we study inherited neuropathies, which reveal important determinants of myelin formation. Recently, we have produced/studied seven mouse models of Myelin Protein Zero (MPZ) neuropathies that
cause widely varying neuropathy phenotypes in patients. Mice overexpressing wildtype P0 develop
congenital hypomyelination; mice expressing P0 with
a myc-epitope tag at the amino terminus unexpectedly model two more severe subtypes of
CMT1B neuropathy; and mice expressing P0 with
any of five known human MPZ mutations model
CMT1B or Congenital Hypomyelination Neuropathy.
We validated these models, confirmed that the mutations operate through gain of function, and
showed that the mutant proteins have their “toxic”
effect from various locations in the Schwann cell,
many times away from myelin itself. For example, in
MpzS63del mice, mutant P0 is retained in the endoplasmic reticulum (Figure 31) and activates pro-
tein quality control pathways in myelinating Schwann
cells of peripheral nerve. Our recent data suggest
that protein quality control alters trafficking of the P0
wildtype counterpart, the translation of myelin proteins, or impairs proteasome degradation of myelin
proteins, thereby impairing myelin stability in CMT
nerves. More recently, we have strong evidence that
endoplasmic reticulum stress alters translational
homeostasis of myelinating Schwann cells, and this
could explain the developmental defect seen in
S63del nerves. In addition, in another model of
CMT1B, MpzR98C, we found that endoplasmic
reticulum stress alters the balance of Krox20 and
cJUN transcription factors that regulate differentiation of myelinating Schwann cells. Another mutant
P0 protein, P0Q215X, may be mistrafficked to the
surface of Schwann cells where it may interfere with
appropriate signals from its extracellular matrix. Finally, P0S63C may form oxidized dimers in trans in
the myelin sheath, altering the fluidity of the myelin
sheath. These data reveal both pathogenesis of neuropathy, and biological clues about the normal myelination.
Lawrence Wrabetz
191
DIVISION OF GENETICS AND CELL BIOLOGY
Research Units
Figure 31. P0S63del is retained in the endoplasmic reticulum of myelinating Schwann cells in S63del
sciatic nerve.
Biomolecular mass spectrometry Unit
The Unit was closed down in 2013 following the
relocation of Angela Bachi to IFOM in Milan.
The unit has applied technological innovations in
proteomics to achieve a comprehensive qualitative and quantitative description of complex mo-
lecular mechanisms. In particular, the unit focused
on novel proteomic approaches that can be applied to cells under physiological and pathological
states.
Marco E. Bianchi
European Institute for Research in Cystic Fibrosis (IERFC)
Cystic fibrosis (CF) patients harboring the most common F508del-CFTR mutant are poor responders to
potentiators of CFTR channel activity. Misfolded
F508del-CFTR can be rescued at the cell surface
by pharmacological agents (correctors) preventing
its intracellular retention and degradation, but it is rapidly dismissed from the plasma membrane (PM) and
redirected from endosomal recycling towards lysosomal degradation. A number of CFTR-corrector
molecules have been identified by highthroughput
screening, but their efficacy in ameliorating the CF
lung phenotype in pre-clinical models or in CF patients, is controversial. Restoration of a functional proteostasis network by proteostasis regulators (PRs)
is a novel approach to correct protein misfolding in
conformational diseases, among which CF constitutes the quintessential example. We previously reported that defective CFTR function induces reactive oxygen species-dependent and transglutaminase-2-mediated sequestration of BECN1, leading
to defective autophagy and increased lung inflammation. Our results provide evidence that functional
perturbation of CFTR affects endosomal trafficking
of cell-surface proteins, in turn sequestrating
BECN1. This leads to local generation of PtdIns3P,
which is pivotal in regulating endosomal fusion/maturation and trafficking, and to disabled autophagy.
We demonstrated that PRs can rescue F508delCFTR trafficking and stabilize a functional CFTR mutant at the PM in primary bronchial epithelial cells,
in brushed nasal epithelial cells from CF patients and
in F508del-CFTR homozygous mice. The effects of
cystamine extend well beyond drug washout thus
enabling the beneficial action of CFTR potentiators
in controlling lung inflammation. These results outline a novel approach for the treatment of CF indicating that prior re-establishment of autophagy prolongs the PM residence of a sufficient amount of
F508del-CFTR to facilitate the action of CFTR potentiators. Our data suggest that a functional CFTR
might orchestrate peripheral proteostasis and regulate its own PM residence and function. Moreover,
manipulating the cellular mechanisms that ultimately link protein misfolding to protein malfunction,
might constitute a therapeutic strategy for the
treatment of conformational diseases.
Luigi Maiuri
DIVISION OF GENETICS AND CELL BIOLOGY
Genetics of common disorders Unit
Genetics of complex disorders: toward a personalized medicine
The projects of the Unit aim at the elucidation of
genetic loci underlying the risk for complex disorders by analysis of the genome of genetically isolated populations and case control cohorts from
the general population. We have collected a large
set of clinical and family data of 1800 descendants from the ancient founders of a genetically
isolated population living in a valley in the Apennine, Val Borbera (VB) and we have established a
network of Italian Genetic Isolates (INGI) largely
representative of the general Italian population.
With the information deriving from the dense
genotypes of >5000 people we were able to participate in international consortia and contribute to
the identification of common variants and genetic
loci responsible for complex phenotypes and disease risks, including fertility and reproduction, thyroid pathology, kidney disorders, blood pressure,
tumors of the elderly, iron parameters and blood
cells parameters, food preferences and others.
Among the phenotypes studied we were directly
involved in the genetics of reproductive traits, with
special interest in menopause age and its extremes, Early Menopause (EM) and Premature
Ovarian Insufficiency (POI), traits that have become
relevant due to the postponement of first child
bearing in all developed countries and the consequent infertility problems. We have identified several genes associated to age of menopause and to
the risk of EM and POI. We were also directly involved on the study of genetics of Anti Mullerian
Hormone (AMH) and of thyroid disorders and we
have recently completed the first meta analysis of
common variants associated to thyroid stimulating
hormone (TSH) and anti-thyroid peroxidase (antiTPO) antibodies. Larger meta analysis are ongoing
and they include less common and rare variants
identified from imputation of sequenced DNAs of
different origin, also from the INGI populations. This
kind of studies are expected to better explain the
risk of early menopause and to provide genetic
markers that can be used to establish protocols for
personalized medicine.
Daniela Toniolo
Intracellular signaling pathways Unit
Live cell imaging of endoplasmic reticulum stress sensing
Homeostasis of the protein folding machinery in
the endoplasmic reticulum (ER) is maintained via
unfolded protein response (UPR) pathways that in
large part are conserved in all eukaryotes. Like all
stress responses, the UPR allows cells to adapt
to novel environmental conditions or physiological
needs. When excessive or prolonged, however,
stress responses become maladaptive. The UPR
thus plays a role in several degenerative disorders
and other diseases related to disturbances in ER
function. We established earlier that ER stress
signaling involves clustering of the UPR
sensor/transducer Ire1 in yeast and that this phenomenon is conserved in man. Through insertion
of fluorescent tags GFP and mCherry in the transmembrane UPR transducers, IRE1 and its distant
family member PERK, we have been able to create transgenes that report on ER stress signaling.
By use of lentiviruses we deliver the tagged transgenes. Crucial is that expression levels of the
transgenes can be kept lower or on a par with the
endogenous counterparts as not to alter the circuitry of the UPR. We therefore express fluorescent transgenes under the doxicyclin inducible Tet
promoter. By expressing the tagged transgenes
of UPR transducers in corresponding knockout
cell lines, we have verified that they can restore
downstream signaling, in particular splicing of
xbp-1 in the case of IRE1 and expression of
CHOP in case of PERK, both upon ER stress induction. Using UPR eliciting drugs such as tunicamycin, tagged IRE1 and PERK transgenes
faithfully report on how the endogenous UPR
transducers cluster into foci. Moreover, the two
UPR sensors do not co-cluster, but form distinct
foci. We now employ a second lentiviral inducible
expression system, which is under control of
mifepristone (Mif). As such, we express secretory
IgM heavy chain (µs). In the absence of the light
chain, µs will never be assembled into antibodies,
accumulates in the ER lumen and causes mild ER
stress, as evidenced by xbp-1 splicing. More importantly, µs expression provoked IRE1-GFP clustering–the first proof that UPR sensor clustering
occurs under more physiological (i.e. non-drug induced) ER stress conditions. Our findings will be
useful to study (patho-)physiological conditions of
UPR activation.
Eelco Van Anken
193
DIVISION OF GENETICS AND CELL BIOLOGY
Research Units
Molecular basis of polycystic kidney disease Unit
Unraveling the molecular basis of polycystic kidney diseases and
identification of potential targets for therapy
Polycystic Kidney Diseases (PKD) is a class of
pathologies characterized by abnormally enlarged
tubules eventually causing renal failure. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common form of PKD and a very
frequent genetic disease affecting 1:1000. ADPKD is caused by mutations in either the PKD1 (in
85% of cases) or the PKD2 genes (in 15%) encoding for Polycystin-1 (PC-1), a large plasma
membrane receptor, and Polycystin-2 (PC-2), a
calcium channel, respectively. ADPKD is caused
by loss of function of either of the two genes, but
the normal function of the two genes or why their
loss-of-function causes cystogenesis remains
elusive. Recent identification of signaling cascades de-regulated in ADPKD has led to the initiation of several clinical trials, but an approved
therapy is still lacking. Likewise, the precise molecular mechanism of how a cyst forms is still
lacking. In 2013 we have shown that Polycystin-1
is involved in the establishment of proper tubular
diameter during renal development. Renal tubules
are generated through a very complex and diverse type of events. During embryonic develop-
ment the final diameter of the tubules is established through a mechanism similar to convergent
extension involving cellular intercalation. We have
shown that mice mutants of the Pkd1 gene, encoding for a truncated form of PC-1, show a defect in tubular diameter and in the capability of
cells to properly achieve mediolateral orientation.
We have further shown that PC-1 regulates the
capability of cells to polarize during cell migration.
Finally, we have described that all these activities
of PC-1 are due to its capability to interact with
the Par3/aPKC complex (Castelli et al, Nat
Comm, 2013). During 2013 we have also described a novel alteration in ADPKD which might
be targeted for therapy. We have shown that defective glucose metabolism is intimately involved
in the pathobiology of ADPKD and we have provided evidence that a glucose analogue, 2-deoxyglucose (2DG) has a beneficial effect on
murine models of the disease providing a strong
rationale for a novel therapeutic approach (Rowe
et al, Nat Med, 2013).
Alessandra Boletta
NeuroGlia Unit
Adhesion molecules and signaling in nervous system development and
myelin diseases
Schwann cells and oligodendocytes myelinate
axons, and contribute to neuronal development,
differentiation, integrity and regeneration. All these
functions are modulated by interactions of the glial
cells with the extracellular matrix (ECM) and with
axons. Our laboratory studies these extracellular
interactions and how they can be exploited to facilitate remyelination in neurological diseases.
In 2013 the following goals were achieved:
1) In the ECM, laminins regulates myelination and
permit axonal sorting, the process by which large
axons are segregated by a single Schwann cell to
be myelinated. We identified α6β1, α7β1 integrins as the receptors important for radial sorting.
2) By studying the signalling molecules activated
by these receptors, we found that a specific isoform of P38 MAPK represents a potential target
for remyelination, because it inhibits oligodendrocyte myelination and it is overexpressed in brains
from Multiple Sclerosis patients.
3) Another aspect controlled by the ECM in peripheral nerves is the formation of Nodes of Ranvier. In peripheral neuropathies due to laminin deficiency patients have abnormal clustering of voltage-gated-sodium channels at Nodes. These effects are mediated by the receptor dystroglycan.
We showed that dystroglycan recruits perlecan at
nodes, which in turn binds gliomedin, a molecule
required for clustering of sodium channels
4) Sodium channels are also clustered at the axon initial segment (AIS), the region where action
potentials are generated. We are investigating the
role of a guanosine exchange factor for the small
GTPase ARF6, in the clustering of sodium channels at the AIS and in the establishment of the AIS
compartment.
5) By performing epistasis experiments in mice
we have shown that laminins prevents myelination
driven by the growth factor neuregulin in fibers
that should not be myelinated, either because
DIVISION OF GENETICS AND CELL BIOLOGY
they are not at the correct developmental time or
because they are too small.
6) Only few molecules that mediate interactions
between glial cells and axons are known. Using a
subfractionation in vitro system and proteomic we
have identified novel molecules that prevents
myelination when they are deleted in mice.
Maria Laura Feltri
Figure 32. Perlecan and gliomedin induce the formation of sodium channel clusters (red) on axons from
dorsal root ganglia sensory neurons (cyan blue).
195
DIVISION OF GENETICS AND CELL BIOLOGY
Research Units
Regulation of iron metabolism Unit
Our Unit is involved in the study of systemic iron
homeostasis and especially in the relationship between iron and erythropoiesis. In the last years we
focused on transferrin receptor 2 (TfR2), a transmembrane protein, mainly expressed in the liver
and in the erythroid precursors, that is mutated in
hemochromatosis type 3, a rare recessive disorder leading to iron overload. Liver TfR2 activates
hepcidin (HAMP) transcription in response to increased plasma iron, although the molecular
mechanism remains uncertain. In erythroid cells
TfR2 associates with the erythropoietin receptor
(EpoR) and is required for its surface transport.
TfR2 knockdown in vitro delays the erythroid terminal differentiation (Foretnikova et al, Blood
2010;116:5357-67). To discriminate between liver
and erythroid function of Tfr2 we first crossed iron
deficient mice lacking the hepcidin inhibitor transmembrane serine protease 6 (Tmprss6-/-) with
Tfr2 total (Tfr2-/-) or liver-specific (Tfr2LCKO)
knockout animals. All double KO animals have iron
deficiency as Tmprss6-/-, demonstrating that liver
TfR2 acts upstream TMPRSS6, but only mice with
complete Tfr2-/- develop erythrocytosis, in the
presence of normal Epo levels suggesting that this
was consequent to the loss of erythroid Tfr2 (Nai et
al Haematologica DOI: 10.3324/haematol.2013.103143). In order to better clarify this finding, in collaboration with G. Ferrari at Tiget, we have
generated a mouse specifically lacking Tfr2 in the
erythropoietic compartment by transplanting (T)
wild-type animals with the bone marrow (BM) of
Tfr2-/- donors. Four months after BMT mice transplanted with Tfr2-/- BM have normal iron homeostasis, normal Epo levels but higher hemoglobin
and red cell count than animals transplanted with
wild type BM. BM conditional Tfr2-/- have higher
number of nucleated erythroid precursors, which
show decreased apoptosis. Our results suggest
that erythroid cells have increased Epo sensitivity in
the absence of TfR2, in keeping with its function of
EpoR partner. We propose that TfR2 is a limiting
factor for erythropoiesis especially in conditions of
iron-restriction through mechanisms that are under
investigation.
Clara Camaschella
Molecular genetics of renal disorders Unit
Our main reserch interest is to understand the
role of uromodulin in renal function and in chronic
diseases of the kidney. Uromodulin, the most
abundant protein found in urine, is exclusively expressed in the kidney by the thick ascending limb
(TAL) of Henle’s loop and plays a protective role
against urinary tract infections and calcium oxalate crystals-induced damage (Rampoldi et al,
Kidney Int 2011).
Mutations in the uromodulin gene UMOD lead to
uromodulin-associated kidney disease (UAKD),
an autosomal dominant disease characterised by,
tubulo-interstitial nephritis and renal failure. We
demonstrated that uromodulin mutations have a
gain-of-function effect as they lead to retention of
mutant protein in the ER (Bernascone et al, Hum
Mol Genet 2010). This is a key pathogenetic
event, eventually leading to TAL damage, inflammation and fibrosis.
Interestingly, common variants in the UMOD gene
have been shown to give independent susceptibility for chronic kidney disease (CKD) and hypertension in several genome-wide association studies (GWAS). Such variants map in the UMOD
gene promoter and are in full linkage disequilibrium. We recently demonstrated that UMOD risk alleles are associated with increased levels of urinary uromodulin and directly increase gene expression in vitro and in vivo (Trudu et al, Nat Med
2013). We modeled this effect in transgenic mice
and showed that uromodulin overexpression
leads to salt-sensitive hypertension and to agedependent renal lesions that are similarly observed in elderly subjects homozygous for UMOD
risk variants. We demonstrated that the link between uromodulin and hypertension is caused by
activation of the renal sodium co-transporter
NKCC2. This mechanism is relevant in humans,
as pharmacological inhibition of NKCC2 is more
effective in lowering BP in hypertensive patients
homozygous for UMOD risk variants. Our findings
establish a link between the genetic susceptibility
to hypertension and CKD, the control of uromodulin expression and its role in salt-reabsorption in
the TAL segment. These data point to uromodulin
as a novel therapeutic target to lower BP and preserve renal function.
Luca Rampoldi
DIVISION OF GENETICS AND CELL BIOLOGY
Clinical Research Units
Dento-facial histopathology Unit
Biomaterials and implant-prosthetic rehabilitations in dentistry
Our activity focused on biological features and clinical applications of bone substitues and dental implants for oral rehabilitations. Moreover, we studied
histological features of bone healing in oral surgery
procedures. To evaluate the different behavior of 3dimensional biomaterial scaffolds-Bovine Bone (BB;
Bio-Oss) and Hydroxyapatite (HA;ENGIpore)-during
initial bone healing and development. Human dental papilla stem cells (hDPaSCs) were selected with
FACsorter cytofluorimetric analysis, cultured with
osteogenic medium, and analyzed with Alizarin red
stained after differentiation. The obtained osteoblast-like cells (OCs) were cultured with BB and
HA. alkaline phosphatase (ALP), OC, MEPE, and
runt-related transcription factor 2 (RUNX2) expression markers were investigated performing Western
blot and reverse transcription-polymerase chain
reaction (RT-PCR) analysis. After 40 days, samples
were analyzed by light and electron microscopy. All
the samples showed high in vitro biocompatibility
and qualitative differences of OCs adhesion. RTPCR and Western blot data exhibited similar marker
rate, but ALP, OC, MEPE, and RUNX2expression,
during initial healing and bone regeneration phase,
was higher and faster in human dental papilla onto
BB than in HA scaffolds. In biomaterials growth,
RUNX2 seems to play an important role as a key
regulator in human OCs from dental papilla bone
development. Different surface BB scaffold characteristics seem to play a critical role in OCs differentiation showing different time of bone regeneration morphological characteristics as well as
higher and faster levels of all observed markers.
Moreover, we studied innovative and microinvasive implant-prosthodontics procedures from a clinical point of view. In clinical studies we also investigated the use of a magnetic mallet in bone
condensing procedures, lowering postoperative
complications, and testing new dental implant materials, as sandblasted and acid etched titanium
surfaces. In conclusion, we focused our clinical activity on new implant surgical protocols, to shorten
treatment time (e.g. immediate loading procedures)
and improve the outcome, applying esthetic and
functional prostheses.
Enrico Gherlone
Genomics of renal diseases and hypertension Unit
1. Pharmacogenomics (PGX) of Hypertension
In hypertensive population only 1/3 of patients reaches blood pressure (BP) targets with the main classes of anti-hypertensive drugs. This variability is, in
part, under genetic control. PGX aims to identify genetic markers predicting the individual drug response.
We evaluated two current anti-hypertensive drugs:
Hydrochlorothiazide (HCTZ) and Perindopril (ACEi).
Polymorphisms of genes affecting renal sodium
transport and signaling (NKAIN2, NKAIN3, NEDD4L,
WNK1, SLC12A3; SLC12A1, SIK1, EGFR), drug
metabolism (CYP7A1), vasodilation state (CPS1,
PRKG1, ITPR2, MYO16), dopaminergic and RAAS
systems (DRD1; REN) associated to BP decrease
after 4 weeks of therapy. We developed two pathway-based algorithms to create genetic profiles of
response to HCTZ and ACEi in naïve hypertensive
patients (see figure). This innovative approach allows
an a priori choice of the treatment in hypertensive
patients.
2. Acute Kidney Injury (AKI) predicting model
AKI is a frequent complication of cardiac surgery.
We focused on milder AKI not requiring dialysis
(AKI-ND), which is very common and contributes
to several in-hospital outcomes.
High pre-operative Endogenous Ouabain (EO)
levels, an adrenal stress hormone with hemodynamic and renal effects, are associated with a
worse renal outcome after cardiac surgery. We
developed two risk models of AKI-ND using both
clinical aspects, based on 8 pre-operative variables, (CLIN-AKI) and the EO plasma levels
(CLIN-EO-AKI). Both these models are straightforward, useful and readily applicable at the bedside
to provide more precisely the relative risk of development of AKI after cardiac surgery.
3. Salt-inducible kinase 1 (SIK1) and Nephrin
Nephrin is a crucial component of the slit diaphragm. We linked Adducin, a cytoskeletal protein,
and EO levels to hypertension and, through nephrin
down-regulation, to kidney injury. We discovered that
SIK1 colocalizes with nephrin in podocytes. SIK1
may act as a component of the slit diaphragm membrane required to maintain the filtration barrier functions of glomerular podocytes, facilitating nephrin signaling activities. rs3746951 SIK1 polymorphism has
been associated with hypertension that may also affect nephrinuria, a potential new marker for kidney
injury development.
Paolo Manunta
197
DIVISION OF GENETICS AND CELL BIOLOGY
Clinical Research Units
Figure 33. Effect on Systolic Blood Pressure (SBP) response after 4 weeks of HCTZ or ACEi treatment:
all patients in light blue box plot, according to the absence (white, Profile NO) or presence (green, Profile YES) of the respective genetic profiles. A genetic profile is the combination of genotypes of pathwaybased genes associated to phenotype. The box plot graph summarizes the statistical measures (median, the 75th and 25th percentiles, and minimum and maximum data values) of the distribution of the
SBP decreases (mmHg). OR= Odds ratio.
Reproductive sciences Lab
Molecular and genetic aspects of female infertility
Endometriosis, an estrogen-dependent chronic
inflammatory disease characterized by the ectopic growth of endometrial tissue, is the most
frequent occurrence in infertile women. In affected
women, granulosa cells, the sex steroid producing cells in the ovarian follicle, undergo apoptosis
in vitro. A dysregulation of the WNT/β-catenin signaling pathway and an aberrant gene expression
of the downstream targets survivin and BMP4
suggest a role of this pathway in granulosa cell
atresia (Sanchez et al, Fertil Steril 2014). A most
common form of endometriosis is characterized
by the presence of one or more ovarian cysts
containing high concentrations of cellular stress
factors, including iron (Sanchez et al, Hum Reprod Update 2013; Sanchez et al, Reprod Sci
2014). We have shown that the lower numbers of
oocytes retrieved from follicles adjacent to the
cyst are associated with increased iron levels, ex-
pression of its major storage protein H/L ferritin in
the follicular fluid and increased expression of H
ferritin and transferrin receptor-1 in the granulosa
cells (Sanchez et al., Hum Reprod 2014). Our results demonstrate that the ovary has the ability to
store excess iron, however prevention of ovarian
iron overload is needed to allow the maturation of
a functional oocyte.
We are also interested in the identification of novel
genetic risk factors for endometriosis (Pagliardini
et al, J Med Genet 2013). In a replication study
(305 endometriosis and 2710 controls) we have
shown that the SNP located near the VEZT gene
(coding for vezatin, adherens junctions protein) is
strongly associated with endometriosis (p=2x105). Ongoing analysis of VEZT expression and
function will provide new insights into the pathogenesis of the disease.
Premature ovarian failure can also be induced by
DIVISION OF GENETICS AND CELL BIOLOGY
chemotherapy. We demonstrated that human
granulosa cells treated in vitro with doxorubicin or
paclitaxel undergo rapid apoptosis, downregulate
ERβ and FSHR expression, and switch off the
WNT3/β-catenin signaling pathway. Restoration
of the β-catenin signaling, by inhibiting its proteo-
somal degradation, protects granulosa cells from
chemotoxicity (Sanchez et al, Toxicol Sci 2013).
This approach will help to identify novel molecular
targets to limit chemotherapy-induced gonadotoxicity.
Paola Panina
Tissue engineering and biomaterials
Tissue engineering studies for osteo-cartilaginous, meniscal and tendon
tissue
Our research activity focuses on the development
of tissue engineering strategies for the repair and
regeneration of damaged structural tissues. In this
regard, articular cartilage, meniscus tissue and
tendon tissue do not possess innate capacity of
self-repair. Additionally, some clinical situation involves the lack of bone tissue. We have devel-
oped of an engineered osteochondral composite
for the repair of the cartilage and osteo-chondral
lesions and tested in pre-clinical model demonstrating the great potential of such a material in
the repair of these complex lesions.
Having as ultimate goal the developing an engineered meniscal substitute, we are also conduct-
Figure 34. Collagen I and collagen II double immunofluorescent staining of engineered cartilage samples (collagen II in red, collagen I in green). Samples at 1 week of culture; many chondrocytes are immunopositive to collagen II in the cytoplasm (red) and are immersed in an intensely collagen II immunopositive ECM (red), while a very scarce immunoreactivity to collagen I (green) is evident in the fibrin
glue, as evidenced by the co-expression of both collagen types (yellow stain in the bottom of the image). This image has been published as cover image in the March 2014 issue of the journal Tissue Engineering - Part A.
199
DIVISION OF GENETICS AND CELL BIOLOGY
Clinical Research Units
ing a series of experiments with the attempt of
characterizing the native juvenile and adult meniscus. We have demonstrated the presence of at
least three cell lines within the meniscus tissue
and a different biochemical composition in the
young and adult meniscus. These data may represent the base for meniscus tissue engineering.
On this regard, adipose derived stem cells (ASC)
have been tested as possible source for engineering this important structure.
We are also conducting a series of experiments
with the goal of create a tissue engineered tendon. We believe that a tendon engineered in vitro
with a biological scaffold seeded with autologous
fibroblasts could represent an important solution.
As possible cell source, we have tested tendon,
ligament, peritenon and dermal fibroblasts. Once
the ideal cell source and culture condition will be
identified, pre-clinical studies will be conducted in
order to test the potential of this model. In collaboration with the University Hospital Basel, Basel,
Switzerland, we have developed a strategy for
bone tissue engineering based on the recapitulation of the embryonic paths during the bone formation through the endochondral ossification
process. Several studies are on their way for the
characterization of the newly bone formed in a
heterotopic environment and test the potential for
clinical applications.
Giuseppe M. Peretti
DIVISION OF GENETICS AND CELL BIOLOGY
Selected publications
Berndt, SI; Gustafsson, S; Magi, R; Ganna, A; Wheeler, E; Feitosa, MF; Justice, AE; Monda, KL;
Croteau-Chonka, DC; Day, FR; Esko, T; Fall, T; Ferreira, T; Gentilini, D; Jackson, AU; Luan, J; Randall, JC; Vedantam, S; Willer, CJ; Winkler, TW; Wood, AR; Workalemahu, T; Hu, YJ; Lee, SH;
Li,ang, L; Li,n, DY; Min, JL; Neale, BM; Thorleifsson, G; Yang, J; Albrecht, E; Amin, N; Bragg-Gresham, JL; Cadby, G; Heijer, MD; Eklund, N; Fischer, K; Goel, A; Hottenga, JJ; Hu,ffman; JE; Jarick,
I; Johansson, A; Johnson, T; Kanoni, S; Kleber, ME; Konig, IR; Kristiansson, K; Kutalik, Z; Lamina,
C; Lecoeur, C; Li, G; Mangino, M; McArdle, WL; Medina-Gomez, C; Muller-Nurasyid, M; Ngwa, JS;
Nolte, IM; Paternoster, L; Pechlivanis, S; Perola, M; Peters, MJ; Preuss, M; Rose, LM; Shi, J; Shungin, D; Smith, AV; Strawbridge, RJ; Surakka, I; Teumer, A; Trip, MD; Tyrer, J; Van Vliet-Ostaptchouk,
JV; Vandenput, L; Waite, LL; Zhao, JH; Absher, D; Asselbergs, FW; Atalay, M; Attwood, AP; Balmforth, AJ; Basart, H; Beilby, J; Bonnycastle, LL; Brambilla, P; Bruinenberg, M; Campbell, H; Chasman, DI; Chines, PS; Collins, FS; Connell, JM; O Cookson, W; De Faire, U; De Vegt, F; Dei, M;
Dimitriou, M; Edkins, S; Estrada, K; Evans, DM; Farrall, M; Ferrario, MM; Ferrieres, J; Franke, L;
Frau, F; Gejman, PV; Grallert, H; Gronberg, H; Gudnason, V; Hall, AS; Hall, P; Hartikainen, AL; Hayward, C; Heard-Costa, NL; Heath, AC; Hebebrand, J; Homuth, G; Hu, FB; Hu,nt; SE; Hypponen, E;
Iribarren, C; Jacobs, KB; Jansson, JO; Jula, A; Kahonen, M; Kathiresan, S; Kee, F; Khaw, KT; Kivimaki, M; Koenig, W; Kraja, AT; Kumari, M; Kuulasmaa, K; Kuusisto, J; Laitinen, JH; Lakka, TA; Langenberg, C; Launer, LJ; Lind, L; Lindstrom, J; Liu, J; Liuzzi, A; Lokki, ML; Lorentzon, M; Madden,
PA; Magnusson, PK; Manunta, P; Marek, D; Marz, W; Leach, IM; McKnight, B; Medland, SE; Mihailov, E; Milani, L; Montgomery, GW; Mooser, V; Muhleisen, TW; Munroe, PB; Musk, AW; Narisu,
N; Navis, G; Nicholson, G; Nohr, EA; Ong, KK; Oostra, BA; Palmer, CN; Palotie, A; Peden, JF; Pedersen, N; Peters, A; Polasek, O; Pouta, A; Pramstaller, PP; Prokopenko, I; Putter, C; Radhakrishnan,
A; Raitakari, O; Rendon, A; Rivadeneira, F; Rudan, I; Saaristo, TE; Sambrook, JG; Sanders, AR;
Sanna, S; Saramies, J; Schipf, S; Schreiber, S; Schunkert, H; Shi,n; SY; Signorini, S; Sinisalo, J;
Skrobek, B; Soranzo, N; Stancakova, A; Stark, K; Stephens, JC; Stirrups, K; Stolk, RP; Stumvoll,
M; Swift, AJ; Theodoraki, EV; Thorand, B; Tregouet, DA; Tremoli, E; Van Der Klauw, MM; Van Meurs,
JB; Vermeulen, SH; Viikari, J; Virtamo, J; Vitart, V; Waeber, G; Wang, Z; Widen, E; Wild, SH; Willemsen, G; Winkelmann, BR; Witteman, JC; Wolffenbuttel, BH; Wong, A; Wright, AF; Zillikens, MC;
Amouyel, P; Boehm, BO; Boerwinkle, E; Boomsma, DI; Caulfield, MJ; Chanock, SJ; Cupples, LA;
Cusi, D; Dedoussis, GV; Erdmann, J; Eriksson, JG; Franks, PW; Froguel, P; Gieger, C; Gyllensten,
U; Hamsten, A; Harris, TB; Hengstenberg, C; Hicks, AA; Hingorani, A; Hinney, A; Hofman, A; Hovingh, KG; Hveem, K; Illig, T; Jarvelin, MR; Jockel, KH; Keinanen-Kiukaanniemi, SM; Kiemeney, LA;
Kuh, D; Laakso, M; Lehtimaki, T; Levinson, DF; Martin, NG; Metspalu, A; Morris, AD; Nieminen, MS;
Njolstad, I; Ohlsson, C; Oldehinkel, AJ; Ouwehand, WH; Palmer, LJ; Penninx, B; Power, C;
Province, MA; Psaty, BM; Qi, L; Rauramaa, R; Ridker, PM; Ripatti, S; Salomaa, V; Samani, NJ;
Snieder, H; Sorensen, TI; Spector, TD; Stefansson, K; Tonjes, A; Tuomilehto, J; Uitterlinden, AG;
Uusitupa, M; Van Der Harst, P; Vollenweider, P; Wallaschofski, H; Wareham, NJ; Watkins, H; Wichmann, HE; Wilson, JF; Abecasis, GR; Assimes, TL; Barroso, I; Boehnke, M; Borecki, IB; Deloukas,
P; Fox, CS; Frayling, T; Groop, LC; Haritunian, T; Heid, IM; Hu,nter; D; Kaplan, RC; Karpe, F; Moffatt, MF; Mohlke, KL; O’Connell, JR; Pawitan, Y; Schadt, EE; Schlessinger, D; Steinthorsdottir, V;
Strachan, DP; Thorsteinsdottir, U; Van Duijn, CM; Visscher, PM; Di Blasio, AM; Hirschhorn, JN;
Li,n,dgren; CM; Morris, AP; Meyre, D; Scherag, A; McCarthy, MI; Speliotes, EK; North, KE; Loos,
RJ; Ingelsson, E. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and
provides insights into genetic architecture. Nature Genet.: 2013; 45(5): 501-512 - Article
IF 2012: 35,209
Bertolotti, M and Bestetti, S and García-Manteiga, JM and Medraño-Fernandez, I; Dal Mas,
A; Malosio, ML; Sitia, R. Tyrosine kinase signal modulation: a matter of H2O2 membrane permeability? Antioxid. Redox Signal.: 2013; 19(13): 1447-1451 - Review
IF 2012: 7,189
Camaschella, C. Treating iron overload. New Engl. J. Med.: 2013; 368(24): 2325-2327 - Article
IF 2012: 51,658
Castelli, M; Boca, M; Chiaravalli, M; Ramalingam, H; Rowe, I; Distefano, G; Carroll, T; Boletta,
A. Polycystin-1 binds Par3/aPKC and controls convergent extension during renal tubular morphogenesis. Nat. Commun.: 2013; 4: 2658 - Article
IF 2012: 10,015
201
DIVISION OF GENETICS AND CELL BIOLOGY
Selected publications
Citterio, L and Ferrandi, M; Delli Carpini, S; Simonini, M; Kuznetsova, T; Molinari, I; Dell’Antonio, G; Lanzani, C; Merlino, L; Brioni, E; Staessen, JA; Bianchi, G; Manunta, P. cGMP-dependent protein kinase 1 polymorphisms underlie renal sodium handling impairment. Hypertension:
2013; 62(6): 1027-1033 - Article
IF 2012: 6,873
D’Antonio, M; Musner, N; Scapin, C; Ungaro, D; Del Carro, U; Ron, D; Feltri, ML; Wrabetz, L.
Resetting translational homeostasis restores myelination in charcot-marie-tooth disease type 1B
mice. J. Exp. Med.: 2013; 210(4): 821-838 - Article
IF 2012: 13,214
Dormoy-Raclet, V and Cammas, A; Celona, B; Lian, XJ; Van Der Giessen, K; Zivojnovic, M;
Brunelli, S; Riuzzi, F; Sorci, G; Wilhelm, BT; Marco, SD; Donato, R; Bianchi, ME; Gallouzi, IE. HuR
and miR-1192 regulate myogenesis by modulating the translation of HMGB1 mRNA. Nat. Commun.: 2013; 4: 2388 - Article
IF 2012: 10,015
Kottgen; A; Albrecht, E; Teumer, A; Vitart, V; Krumsiek, J; Hundertmark, C; Pistis, G; Ruggiero, D;
O’Seaghdha, CM; Haller, T; Yang, Q; Tanaka, T; Johnson, AD; Kutalik, Z; Smit,h, AV; Shi, J;
Struchalin, M; Middelberg, RPS; Brown, MJ; Gaffo, AL; Piras,tu, N; Li, G; Hayward, C; Zemunik, T;
Huffman, J; Yengo, L; Zhao, JH; Demirkan, A; Feitosa, MF; Li,u; X; Malerba, G; Lopez, LM; Van Der
Harst, P; Li, X; Kleber, ME; Hicks, AA; Nolte, IM; Johansson, A; Murgia, F; Wild, SH; Bakker, SJL;
Peden, JF; Dehghan, A; Steri, M; Tenesa, A; Lagou, V; Salo, P; Mangino, M; Rose, LM; Lehtimaki,
T; Woodward, OM; Okada, Y; Tin, A; Muller, C; Oldmeadow, C; Putku, M; Czamara, D; Kraft, P;
Frogheri, L; Thun, GA; Grotevendt, A; Gislason, GK; Harris, TB; Launer, LJ; McArdle, P; Shuldiner,
AR; Boerwinkle, E; Coresh, J; Schmidt, H; Schallert, M; Martin, NG; Montgomery, GW; Kubo, M;
Nakamura, Y; Tanaka, T; Munroe, PB; Samani, NJ; Jacobs, DR; Li,u; K; D’Adamo, P; Ulivi, S; Rotter,
JI; Psaty, BM; Vollenweider, P; Waeber, G; Campbell, S; Devuyst, O; Navarro, P; Kolcic, I; Hastie, N;
Balkau, B; Froguel, P; Esko, T; Salumets, A; Khaw, KT; Langenberg, C; Wareham, NJ; Isaacs, A;
Kraja, A; Zhang, Q; Wild, PS; Scott, RJ; Holliday, EG; Org, E; Viigimaa, M; Bandinelli, S; Metter, JE;
Lupo, A; Trabetti, E; Sorice, R; Doring, A; Lattka, E; Strauch, K; Theis, F; Waldenberger, M; Wichmann, HE; Davies, G; Gow, AJ; Bruinenberg, M; Stolk, RP; Kooner, JS; Zhang, W; Winkelmann,
BR; Boehm, BO; Lucae, S; Penninx, BW; Smit, JH; Curhan, G; Mudgal, P; Plenge, RM; Portas, L;
Persico, I; Kirin, M; Wilson, JF; Leach, IM; Van Gilst, WH; Goel, A; Ongen, H; Hofman, A; Rivadeneira, F; Uitterlinden, AG; Imboden, M; Von Eckardstein, A; Cucca, F; Nagaraja, R; Piras, MG;
Nauck, M; Schurmann, C; Budde, K; Ernst, F; Farrington, SM; Theodoratou, E; Prokopenko, I;
Stumvoll, M; Jula, A; Perola, M; Salomaa, V; Shin, SY; Spector, TD; Sala, C; Ridker, PM; Kahonen,
M; Viikari, J; Hengstenberg, C; Nelson, CP; Meschia, JF; Nalls, MA; Sharma, P; Singleton, AB; Kamatani, N; Zeller, T; Burnier, M; Attia, J; Laan, M; Klopp, N; Hillege, HL; Kloiber, S; Choi, H; Pirastu,
M; Tore, S; Probst-Hensch, NM; Volzke, H; Gudnason, V; Parsa, A; Schmidt, R; Whitfield, JB; Fornage, M; Gasparini, P; Siscovick, DS; Polasek, O; Campbell, H; Rudan, I; Bouatia-Naji, N;
Metspalu, A; Loos, RJF; Van Duijn, CM; Borecki, IB; Ferrucci, L; Gambaro, G; Deary, IJ; Wolffenbuttel, BHR; Chambers, JC; Marz, W; Pramstaller, PP; Snieder, H; Gyllensten, U; Wright, AF; Navis, G;
Watkins, H; Witteman, JCM; Sanna, S; Schipf, S; Dunlop, MG; Tonjes, A; Ripatti, S; Soranzo, N;
Toniolo, D; Chasman, DI; Raitakari, O; Kao, WHL; Ciullo, M; Fox, CS; Caulfield, M; Bochud, M;
Gieger, C. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat. Genet.: 2013; 45(2): 145-154 - Article
IF 2012: 35,209
Pellegatta, M; De Arcangelis, A; D’Urso, A; Nodari, A; Zambroni, D; Ghidinelli, M; Matafora, V;
Williamson, C; Georges-Labouesse, E; Kreidberg, J; Mayer, U; McKee, KK; Yurchenco, PD; Quattrini, A; Wrabetz, L; Feltri, ML. α6β1 and α7β1 Integrins Are Required in Schwann Cells to Sort
Axons. J. Neurosci.: 2013; 33(46): 17995-18007 - Article
IF 2012: 6,908
Pengo, N; Scolari, M; Oliva, L; Milan, E; Mainoldi, F; Raimondi, A; Fagioli, C; Merlini, A; Mariani, E; Pasqualetto, E; Orfanelli, U; Ponzoni, M; Sitia, R; Casola, S; Cenci, S. Plasma cells require autophagy for sustainable immunoglobulin production. Nat. Immunol.: 2013; 14(3): 298-305 Article
IF 2012: 26,199
DIVISION OF GENETICS AND CELL BIOLOGY
Rowe, I; Chiaravalli, M; Mannella, V; Ulisse, V; Quilici, G; Pema, M; Song, XW; Xu, H; Mari, S;
Qian, F; Pei, Y; Musco, G; Boletta, A. Defective glucose metabolism in polycystic kidney disease
identifies a new therapeutic strategy. Nat. Med. : 2013; 19(4): 488-493 - Letter
IF 2012: 24,302
Sanchez, AM; Giorgione, V; Viganò, P; Papaleo, E; Candiani, M; Mangili, G; Panina-Bordignon, P. Treatment with anticancer agents induces dysregulation of specific Wnt signaling pathways in human ovarian luteinized granulosa cells in vitro. Toxicol. Sci.: 2013; 136(1): 183-192 - Article
IF 2012: 4,328
Trudu, M; Janas, S; Lanzani, C; Debaix, H; Schaeffer, C; Ikehata, M; Citterio, L; Demaretz, S;
Trevisani, F; Ristagno, G; Glaudemans, B; Laghmani, K; Dell’Antonio, G; Swiss Kidney Project on
Genes in Hypertension (SKIPOGH) Team; Bochud, M; Burnier, M; Devuyst, O; Martin, PY; Mohaupt,
M; Paccaud, F; Pechère-Bertschi, A; Vogt, B; Ackermann, D; Ehret, G; Guessous, I; Ponte, B; Pruijm, M; Loffing, J; Rastaldi, MP; Manunta, P; Devuyst, O and Rampoldi, L. Common noncoding
UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression. Nat. Med.: 2013; 19(12): 1655-1660 - Article
IF 2012: 24,302
Vavassori, S and Cortini, M and Masui, S and Sannino, S; Anelli, T; Caserta, IR; Fagioli, C;
Mossuto, MF; Fornili, A; van Anken, E; Degano, M; Inaba, K; Sitia, R. A pH-Regulated Quality
Control Cycle for Surveillance of Secretory Protein Assembly. Mol. Cell: 2013; 50(6): 783-792 - Article
IF 2012: 15,280
Villella, VR; Esposito, S; Bruscia, EM; Vicinanza, M; Cenci, S; Guido, S; Pettoello-Mantovani, M;
Carnuccio, R; De Matteis, MA; Luini, A; Maiuri, MC; Raia, V; Kroemer, G; Maiuri, L. Disease-relevant proteostasis regulation of cystic fibrosis transmembrane conductance regulator. Cell Death Differ.: 2013; 20(8): 1101-1115 - Article
IF 2012: 8,371
203
DIVISION OF GENETICS AND CELL BIOLOGY
Age related diseases
Protein transport and secretion Unit
DIVISION OF GENETICS AND CELL BIOLOGY
Molecular immunology
European Institute for Research in Cystic Fibrosis (IERFC)
205
DIVISION OF GENETICS AND CELL BIOLOGY
Intracellular signaling pathways Unit
Molecular basis of polycystic kidney disease Unit
DIVISION OF GENETICS AND CELL BIOLOGY
Regulation of iron metabolism Unit
Molecular genetics of renal disorders Unit
207
DIVISION OF GENETICS AND CELL BIOLOGY
Research Units
Genomics of renal diseases and hypertension Unit
Tissue engineering and biomaterials
DIVISION OF GENETICS AND CELL BIOLOGY
Reproductive sciences Lab
209
CENTER
FOR
TRANSLATIONAL
GENOMICS
AND BIOINFORMATICS
Director:
Giorgio Casari*
Co-Director:
Elia Stupka
Research Units
Neurogenomics Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 214
HEAD OF UNIT: Giorgio Casari*
RESEARCHERS: Giovanni Lavorgna, Francesca Maltecca*
POST-DOCTORAL FELLOWS: Laura Cassina, Mimma Vizzuso
PHD STUDENT: Francesco Consolato
FELLOW: Elisa Baseggio
TECHNICIAN: Maurizio De Fusco
Genome function Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 215
HEAD OF UNIT: Elia Stupka
RESEARCHERS: Davide Cittaro, Arek Kasprzyck, Dejan Lazarevic, Paolo Provero
POST-DOCTORAL FELLOWS: Silvia Bonfiglio, Gabriele Bucci**, Jose Manuel Garcia-Manteiga,
Francesca Giannese, Michele Loi, Vincenza Maselli, Davide Rambaldi, Michela Riba
FELLOWS: Giulia Barbiera, Iwan Buetti, Stefania Merella, Luca Pandini
TECHNICIANS: Donatella Biancolini, Eleonora Capitolo**, Celia Pardini, Arianna Rezzonico**,
Valeria Rossella, Serenella Sartori
Biomolecular NMR Laboratory (Dulbecco Telethon Institute) –––––––––––––––––––––– 215
HEAD OF UNIT: Giovanna Musco
POST-DOCTORAL FELLOWS: Davide Gaudesi, Michela Ghitti, Valeria Mannella, Andrea
Spitaleri, Chiara Zucchelli
PHD STUDENTS: Andrea Berardi, Dimitrios Spiliotoupulos**
FELLOWS: Giacomo Quilici, Cristina Paissoni
211
CENTER FOR TRANSLATIONAL GENOMICS AND BIOINFORMATICS
Research Units
Genomic Unit for the diagnosis of human pathologies –––––––––––––––––––––––––––––– 216
HEAD OF UNIT: Maurizio Ferrari*
RESEARCHERS: Sara Benedetti, Paola Carrera, Vito Lampasona
FELLOWS: Angela Brisci, Chiara Di Resta, Silvia Galbiati, Stefania Stenirri
TECHNICIAN: Nadia Soriani
Organelle biogenesis and motility Unit ––––––––––––––––––––––––––––––––––––––––––––––––– 217
HEAD OF UNIT: Maria Vittoria Schiaffino
POST-DOCTORAL FELLOWS: Massimo Lazzaro, Ilaria Palmisano
Proteome biochemistry Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 218
HEAD OF UNIT: Massimo Alessio
POST-DOCTORAL FELLOW: Massimo Lazzaro
PHD STUDENTS: Sheila Maria Alvarez-Fernandez, Marco Barbariga, Alan Zanardi**
TECHNICIAN: Antonio Conti
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
CENTER FOR TRANSLATIONAL GENOMICS AND BIOINFORMATICS
Introduction by the Directors
Mission and vision - The Center promotes and contributes genomics and bioinformatics approaches to
biomedicine research. By taking advantage of the excellent clinical environment coupled to outstanding
basic science locally present, the Center works with the San Raffaele Scientific Institute as a whole to advance towards integrative translational research. Biomedicine is quickly transforming the diagnostic and
cure-delivering processes, which are being further enhanced by both –omics and bioinformatics methodologies and the complex network analyses. The Center supports as well as initiates novel, interdisciplinary research that endorses omics-driven translational research approaches. The Center acts as a catalyst
for innovative research projects by complementing existing research lines across the Institute with high
throughput technologies, quantitative methods, and powerful data mining approaches.
Organization - The Center for Translational Genomics and Bioinformatics (CTGB) is located in the DIBIT2
building, and includes 80 scientists. The Center houses six research units, with different expertise ranging from cell biology, protein chemistry, structural biology and genetics, as well as a genome function unit
which is involved in both research and provision of genomics and bioinformatics services.
Goals - The goal of the Center is to produce original research in the fields of translational -omics and bioinformatics, to enrich and enhance research occurring within other divisions and departments with these
disciplines, and to develop novel clinical protocols which bring –omics from bench to bedside.
Achievements
See the Research Unit Reports of:
• Neurogenomics Unit
• Biomolecular NMR Spectroscopy Unit
• Proteome Biochemistry Unit
• Genomic Unit for the Diagnosis of Human Pathologies
• Organelle Biogenesis and Motility Unit
• Genome Function Unit
213
CENTER FOR TRANSLATIONAL GENOMICS AND BIOINFORMATICS
Research Units
Neurogenomics Unit
Three main achievements with translational potential are reported. Spinocerebellar ataxia type
28 (SCA28) is a neurodegenerative disorder characterized by unbalanced standing, gait incoordination, nystagmus, ophthalmoparesis and pyramidal signs. Several disease-causing mutations
have been identified in the AFG3L2 gene. The
haploinsufficient Afg3l2+/- mouse recapitulates
the features of SCA28 patients, displaying motor
incoordination due to dark degeneration of Purkinje cells (PC-DCD).
We estabilished in cultured PCs that Afg3l2-depleted mitochondria ineffectively buffer the
evoked calcium peaks, thus enhancing cytoplasmic calcium levels and finally triggering PC-DCD.
This defect is caused by the negative synergism
between mitochondrial depolarization and altered
trafficking of the organelles to PC dendrites.
These data, besides disclosing the pathogenetic
mechanism of SCA28, demonstrate for the first
time the impact of defective mitochondrial calcium
uptake on local calcium signaling in neurons.
Autosomal dominant cortical myoclonus and
epilepsy (ADCME) is characterized by distal, fairly
rhythmic myoclonus and epilepsy. We have re-
cently demonstrated that a causative mutation of
the α2-adrenergic receptor subtype B (α2B-AR)
associates to ADCME by identifying a novel inframe insertion/deletion in two Italian families. The
mutation alters several conserved residues of the
third intracellular (3i) loop, thus altering the binding
with the scaffolding protein spinophilin upon neurotransmitter activation. This work implicates for
the first time the α-adrenergic system in human
epilepsy and opens new ways for understanding
the molecular pathway of epileptogenesis, widening the spectrum of possible therapeutic targets.
A polymorphisms of the endothelial NO synthase
(eNOS) gene associates with a new variant of
eNOS originating by the skipping of exons 20-21.
This variant is insensitive to calcium stimulation
and displays increased basal NO production. In
fact, carriers of the minor allele express the truncated form of eNOS with altered enzymatic activity that influences NO production and endothelial
function. These findings open to new intriguing
perspectives to several diseases involving vascular response to NO.
Giorgio Casari
Figure 35.
Mitochondria
in Purkinje’s cell
dendrites (green,
caldindin; red,
COX1-mitochondria)
CENTER FOR TRANSLATIONAL GENOMICS AND BIOINFORMATICS
Genome function Unit
The mission of the Genome Function Unit is to
improve our knowledge of genome function and
dysfunction in health and disease. The unit operates on two levels: as a research group undertaking its own original and collaborative research as
well as a unit providing services in both genomics
and bioinformatics within the Institute as well as to
customers and collaborators internationally.
During the 2013, the GFU focused mostly on developing research projects as well as clinical protocols. It consists now of approximately 20 members, with highly interdisciplinary educational
background. The unit operates 2 NGS sequencers, the Illumina HiSeq 2500 and MiSeq,
and utilizes a computing cluster consisting of
~600 CPUs. We processed and analyzed more
than 2,800 samples.
In terms of research the unit has a strong interest
in epigenomics, in particular DNA Methylation. In
this area we have several important collaborations
exploring the heritability of environmentally induced epigenetic traits, some of them involved in
psychiatrics disorder, other in nutrition and allergy,
as for example the FP7 project ATOPICA. In 2013
the Unit also published 13 articles (IF 148,75) and
was involved in 8 awarded grants revolving
around clinical and translational genomics from
the Ministry of Health, in collaboration with other
OSR units as well as external collaborators. The
Unit applied coordinates a COST Action named
CHIP ME, focused on ethical, legal and social issues in genomics. The unit is also actively involved in 2 clinical protocols, one operating on
rare diseases and the other studying the familiar
multiple sclerosis. The unit has worked on the implementation of a web tool for data mining and visualization of large NGS datasets. Last, we collaborated with the unit of Dr. Cirillo to implement a
method to evaluate the feasibility of using sequencing technologies for surveillance of drug resistance in TB and with Dr. Montini at TIGET on
the use of NGS for vector integration analysis.
In terms of service activity the ISO90001 certified
unit provides routine NGS protocols such as sequencing of whole human genomes and exomes,
RNA-Seq, Medip-Seq and aptamer sequencing.
Elia Stupka
Biomolecular NMR Laboratory
We study the structure and dynamics of biomolecular complexes in solution by NMR spectroscopy in combination with a wide range of biochemical, biophysical and computational techniques. Main projects are: 1) Structural characterization of ligand-receptor interactions; 2) Structural and dynamic characterization of chromatin-interacting modules; 3) metabolomics.
1. Integrin αVβ3 is involved in angiogenesis, inflammation, and cancer. It exerts its role interacting with proteins containing an RGD motif. Recent
studies have shown that isoDGR motif can compete with RGD in the binding to αVβ3, paving the
way for isoDGR based drugs. We are currently
working on computational methods (molecular
dynamics, metadynamics, MMPBSA methods) to
predict the conformational effects of the flanking
residues of RGD and isoDGR based cyclopeptides. The effects of the flanking residue on integrin selectivity is also under investigation.
2. Methylation of lysine residues on histone H3
tails regulates transcription. The PHD finger is a
histone binding module able to decode the his-
tone H3 methylated status. We solved the structure of the PHD fingers of Autoimmune Regulator,
a protein expressed in mTEC and responsible for
autoimmune polyendocrinopathy-candidiasisectodermal dystrophy and characterized their
bindingto histone tails by means of biochemical,
biophysical and computational methods. We
have also solved the PHD finger structure of
Sp140 an other transcriptional activator, involved
in CLL and demonstrated that it binds to Prolylisomerase Pin1. We are currently characterizing the
PHD fingers of NSD1 an other transcription factor
involved in Sotos Syndrome and CLL.
3. Metabolomics is an emerging ‘omics’ field that
provides an analytical description of the metabolites in complex biological samples under disparate biological or environmental conditions. Ongoing projects focus on metabolomics of osteolytic lesions (S. Cenci, R4R), metabolic profiling
of PKD1 -/- MEF cells and mice upon pharmacological treatment (Boletta) software development
for multivariate analysis of metabolomics data.
Giovanna Musco
215
CENTER FOR TRANSLATIONAL GENOMICS AND BIOINFORMATICS
Research Units
Figure 36. Solution structure of
Sp140-PHD domain.
Published in: Structure of
human Sp140 PHD finger: An
atypical fold interacting with
Pin1. Zucchelli, C; Tamburri,
S; Quilici, G; Palagano, E;
Berardi, A; Saare, M;
Peterson, P; Bachi, A; Musco,
G. FEBS J.: 2014; 281(1):
216-231 © 2013 FEBS doi:
10.1111/febs.12588
Genomic Unit for the diagnosis of human pathologies
Our investigation is focused to the identification of
new disease genes and to a variety of predisposing sequence variations in order to improve genotype-phenotype correlation in both monogenic and
multifactorial traits. We developed high throughput
genotyping to perform case-control association
studies as well as targeted or exome re-sequencing by Next Generation Sequencing (NGS).
Here we summarize our main results published in
2013: i) in order to classify new variants with respect to their pathogenicity, in-vitro functional
studies were carried out: a variant from migraine
patients was identified in the synprint site of the
CaV2.1 channel which increased function. This
gain-of-function occurs via alterations in inactivation and SNARE protein regulation in the CaV2.1
channel; ii) in order to identify genetic markers for
risk stratification of Brugada Syndrome, we genotyped 73 candidate SNPs in a cohort of 92 patients and correlated the presence of 5 SNPs with
the occurrence of major arrhythmic events by allelic association and survival analysis. This allowed us to elaborate a pilot risk stratification algorithm and a weighted genetic risk score.
Moreover, our research is involved in the analysis
of circulated minority mutated alleles in the plasma of pregnant women to perform noninvasive
prenatal diagnosis through protocols based on
CO-amplification at Lower Denaturation temperature-PCR (COLD-PCR) combined with Sanger
sequencing and highly sensitive microarray substrates which could allow for the detection of fetal
minority sequences without any enrichment strategy. Both these methodologies were also applied
for the detection of KRAS minority mutations in
colon cancer.
A further line of research is focused on the development of tools for the detection of circulating
biomarkers of disease. This include the development of advanced immunoassays for antibody
measurement. These assays were applied to: 1)
the characterization of autoantibody responses
against enterocyte’s autoantigens in the IPEX syndrome, a monogenic disease associated with the
development of severe intestinal autoimmunity; 2)
antibodies to classical diabetes autoantigens; 3)
antibodies to enteroviruses in type 1 diabetes, including in the clinical setting of islet transplantation
in patients.
Maurizio Ferrari
CENTER FOR TRANSLATIONAL GENOMICS AND BIOINFORMATICS
Organelle biogenesis and motility Unit
Our group is focused into the study of secretory
organelle biogenesis and motility in mammalian
cells, as alteration of these processes represents
an important cause of human disease. In particular, we are focused into the study of
melanosomes, i.e. lysosome-related organelles of
pigment cells, devoted to the synthesis, storage
and transport of melanins, and into their aberrant
function in albinism. Indeed, in this genetic disease, melanosomes can lose their ability to synthesize melanin, or can undergo abnormal biogenesis and transport processes. However, in
addition to organelles belonging to the secretory
pathway, mammalian cells also contain other subcellular organelles, such as mitochondria, which
are essential for multiple cellular functions, including ATP production and calcium signaling. Despite the reciprocal crosstalk between different
subcellular organelles and their spatial organization relative to each other is relevant for their proper function, secretory organelles and mitochondria have been traditionally considered distinct. Indeed, physical contacts between mitochondria
and the secretory pathway have been demonstrated so far only with the endoplasmic reticulum
(ER), through structural and functional interorganellar connections. We recently uncovered that
mitochondria physically contact melanosomes as
well, through fibrillar bridges resembling the protein tethers linking mitochondria and the ER (Figure 1). Mitofusin (Mfn) 2, which bridges ER to mitochondria, specifically localises also to
melanosome-mitochondrion contacts, and its
knockdown significantly reduces the interorganellar connections. These contacts are associated
to the melanogenesis process, since they are enhanced both where melanosome biogenesis
takes place in the perinuclear area, and when it is
actively stimulated by OA1, the G protein-coupled
receptor implicated in ocular albinism and organellogenesis. Conversely, the interorganellar
connections are reduced in conditions of abnormal melanosome biogenesis, either due to a primary melanosomal defect, or due to a primary mitochondrial dysfunction. Overall, melanosome-mitochondrion contacts appear relevant for melanogenesis and might play a role in physiological pigmentation and pigmentary diseases.
Maria Vittoria Schiaffino
Figure 37. Three-dimensional
tomographic model of ERmitochondria and
melanosome-mitochondria
interorganellar contacts, as
obtained by manually
contouring the limiting
membranes and internal
structures (melanin fibers and
mitochondrial inner membranes)
of a melanosome (red), a
mitochondrion (yellow) and a
ER tubule (green). Fibrillar
bridges between the
mitochondrion and the ER (light
blue) and between the
mitochondrion and the
melanosome (dark blue) are
shown (modified from: Daniele
et al. Curr. Biol.: 2014; 24(4):
393-403 doi:
10.1016/j.cub.2014.01.007).
217
CENTER FOR TRANSLATIONAL GENOMICS AND BIOINFORMATICS
Research Units
Proteome biochemistry Unit
Onco-proteomics
Serological Proteome Analysis of colorectal carcinoma: Immunologic tolerance is broken in pathologic conditions such as cancer. To identify tumoral antigens, we performed a screening of the
colorectal tumor proteoma by exploiting auto-antibodies contained in the sera of patients. AutoAbs directed against a surface metallo-protease
have been found with high frequency in patients.
Similar reactivity was observed in patients affected by others cancers of epithelial origin, but not in
cancers of hematopoietic origin. The presence of
auto-Abs anti-metalloprotease give an advantages in patients follow up, prolonging the disease-free condition. Auto-Abs affect the metalloprotease function reducing its sheddase activity.
Antibody-based proteomics to study cellular signalling networks: Reverse phase protein microarrays is a technique that allow to analyze the abundance of proteins and their phosphorylation status in patient tumor exploiting specific sets of Abs
able to dissect different signalling pathways. We
are using this approach in B-CLL investigating the
BCR signalling in patients having stable or progressive disease.
By recombinant protein microarray screening we
are also trying to define the reactivity of stereotyped-BCRs cloned from B-CLL patients.
Neuro-proteomics
Protein pattern changes in cerebrospinal fluid
(CSF) of neurodegenerative diseases: Being in
contact with the brain, the CSF analysis is important for pathological processes understanding
and diagnosis. We found that in the CSF of
Parkinson’s (PD) and Alzheimer’s (AD) diseases
the protein ceruloplasmin (Cp) is modified in comparison to healthy subject and others neurological
diseases. The Cp-modifications are due to protein oxidation that causes a decrease in Cp ferroxidase activity, promoting intracellular iron retention in neurons, that contributes to pathological
mechanisms. Now we are studying by mass
spectrometry approach the post-translation modifications induced by the pathological oxidative environment on Cp (e.g. carbonylation, deamidation, thiol oxidation, etc.), and the effects on Cp
functions. In particular we found that deamidation
of the NGR-motifs present in the Cp sequence
promotes loss of ferroxidase function and the gain
of integrin-binding properties.
Massimo Alessio
Figure 38. Molecular dynamic modelling of deamidated ceruloplasmin (in red) docking onto αV/β6 integrin (in
blue). In licorice are shown the most important interactions between the two proteins.
CENTER FOR TRANSLATIONAL GENOMICS AND BIOINFORMATICS
Selected publications
Webb, EA and Almutair, A; Kelberman, D; Bacchelli, C; Chanudet, E; Lescai, F; Andoniadou, CL;
Banyan, A; Alsawaid, A; Alrifai, MT; Alahmesh, MA; Balwi, M; Mousavy-Gharavy, SN; Lukovic, B;
Burke, D; McCabe, MJ; Kasia, T; Kleta, R; Stupka, E; Beales, PL; Thompson, DA; Chong, WK;
Alkuraya, FS; Martinez-Barbera, JP; Sowden, JC; Dattani, MT. ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies. Brain: 2013; 136(10): 3096-3105 - Article
IF 2012: 9,915
Burgoyne, T; Jolly, R; Martin-Martin, B; Seabra, MC; Piccirillo, R; Schiaffino, MV; Futter, CE. Expression of OA1 limits the fusion of a subset of MVBs with lysosomes - a mechanism potentially involved in the initial biogenesis of melanosomes. J. Cell Sci.: 2013; 126(Pt 22): 5143-5152 - Article
IF 2012: 5,877
Condliffe, SB; Fratangeli, A; Munasinghe, NR; Saba, E; Passafaro, M; Montrasio, C; Ferrari, M;
Rosa, P; Carrera, P. The E1015K variant in the synprint region of the CaV2.1 channel alters channel
function and is associated with different migraine phenotypes. J. Biol. Chem.: 2013; 288(47):
33873-33883 - Article
IF 2012: 4,651
Drago, D; Cossetti, C; Iraci, N; Gaude, E; Musco, G; Bachi, A; Pluchino, S. The stem cell secretome and its role in brain repair. Biochimie: 2013; 95(12): 2271-2285 - Review
IF 2012: 3,142
Elvers, KT; Geoghegan, I; Shoemark, DK; Lampasona, V; Bingley, PJ; Williams, AJK. The core cysteines, (C909) of islet antigen-2 and (C945) of islet antigen-2β, are crucial to autoantibody binding in
type 1 diabetes. DIABETES: 2013; 62(1): 214-222 - Article
IF 2012: 7,895
Magnoni, R; Palmfeldt, J; Christensen, JH; Sand, M; Maltecca, F; Corydon, TJ; West, M; Casari,
G; Bross, P. Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency
in mice. Neurobiol. Dis.: 2013; 54: 12-23 - Article
IF 2012: 5,624
Mancini, C; Roncaglia, P; Brussino, A; Stevanin, G; Lo Buono, N; Krmac, H; Maltecca, F; Gazzano,
E; Bartoletti Stella, A; Calvaruso, MA; Iommarini, L; Cagnoli, C; Forlani, S; Le Ber, I; Durr, A; Brice, A;
Ghigo, D; Casari, G; Porcelli, AM; Funaro, A; Gasparre, G; Gustincich, S; Brusco, A. Genome-wide
expression profiling and functional characterization of SCA28 lymphoblastoid cell lines reveal impairment in cell growth and activation of apoptotic pathways. BMC Med. Genomics: 2013; 6: 22 - Article
IF 2012: 3,466
Massa, O and Alessio, M and Russo, L; Nardo, G; Bonetto, V; Bertuzzi, F; Paladini, A; Iafusco, D;
Patera, P; Federici, G; Not, T; Tiberti, C; Bonfanti, R; Barbetti, F. Serological Proteome Analysis
(SERPA) as a tool for the identification of new candidate autoantigens in type 1 diabetes. J. Proteomics: 2013; 82: 263-273 - Article
IF 2012: 4,088
Minelli, C and De Grandi, A; Weichenberger, CX; Gogele, M; Modenese, M; Attia, J; Barrett, JH;
Boehnke, M; Borsani, G; Casari, G; Fox, CS; Freina, T; Hicks, AA; Marroni, F; Parmigiani, G; Pastore, A; Pattaro, C; Pfeufer, A; Ruggeri, F; Schwienbacher, C; Taliun, D; Pramstaller, PP; Domingues,
FS; Thompson, JR. Importance of Different Types of Prior Knowledge in Selecting Genome-Wide
Findings for Follow-Up. Genet. Epidemiol.: 2013; 37(2): 205-213 - Article
IF 2012: 4,015
Parker, J and Tsagkogeorga, G; Cotton, JA; Liu, Y; Provero, P; Stupka, E; Rossiter, SJ. Genomewide signatures of convergent evolution in echolocating mammals. Nature: 2013; 502(7470): 228231 - Letter
IF 2012: 38,597
Privitera, D; Corti, V; Alessio, M; Volonté, A; Lampasona, V; Comi, G; Martino, G; Franciotta,
D; Furlan, R and Fazio, R. Proteomic identification of aldolase A as an autoantibody target in patients with atypical movement disorders. Neurol. Sci.: 2013; 34(3): 313-320 - Article
IF 2012: 1,412
Rowe, I; Chiaravalli, M; Mannella, V; Ulisse, V; Quilici, G; Pema, M; Song, XW; Xu, H; Mari, S;
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CENTER FOR TRANSLATIONAL GENOMICS AND BIOINFORMATICS
Selected publications
Qian, F; Pei, Y; Musco, G; Boletta, A. Defective glucose metabolism in polycystic kidney disease
identifies a new therapeutic strategy. Nat. Med. : 2013; 19(4): 488-493 - Letter
IF 2012: 24,302
Sanges, R; Hadzhiev, Y; Gueroult-Bellone, M; Roure, A; Ferg, M; Meola, N; Amore, G; Basu, S;
Brown, ER; De Simone, M; Petrera, F; Licastro, D; Strahle, U; Banfi, S; Lemaire, P; Birney, E; Muller,
F; Stupka, E. Highly conserved elements discovered in vertebrates are present in non-syntenic loci
of tunicates, act as enhancers and can be transcribed during development. Nucleic Acids Res.:
2013; 41(6): 3600-3618 - Article
IF 2012: 8,278
Sommariva, E; Pappone, C; Martinelli-Boneschi, F; Di Resta, C; Carbone, MR; Salvi, E; Vergara, P; Sala, S; Cusi, D; Ferrari, M; Benedetti, S. Genetics can contribute to the prognosis of
Brugada syndrome: A pilot model for risk stratification. Eur. J. Hum. Genet.: 2013; 21(9): 911-917 Article
IF 2012: 4,319
Vita, F; Lucarotti, V; Alpi, E; Balestrini, R; Mello, A; Bachi, A; Alessio, M; Alpi, A. Proteins from Tuber magnatum Pico fruiting bodies naturally grown in different areas of Italy. Proteome Sci.: 2013;
11: 7 - Article
IF 2012: 2,420
CENTER FOR TRANSLATIONAL GENOMICS AND BIOINFORMATICS
Neurogenomics Unit
Genome function Unit
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CENTER FOR TRANSLATIONAL GENOMICS AND BIOINFORMATICS
Biomolecular NMR Laboratory
Proteome biochemistry Unit
CENTER FOR TRANSLATIONAL GENOMICS AND BIOINFORMATICS
Genomic Unit for the diagnosis of human pathologies
223
EXPERIMENTAL
IMAGING CENTER
Director:
Carlo Tacchetti
Associate Director:
Alessandro Del Maschio*
Research Units
Advanced fluorescence microscopy and nanoscopy research Unit ––––––––––––––– 229
HEAD OF UNIT: Carlo Tacchetti
POST-DOCTORAL FELLOW: Davide Mazza**
Dynamic fluorescence spectroscopy in biomedicine ––––––––––––––––––––––––– 230
GROUP LEADER: Valeria R. Caiolfa
POST-DOCTORAL FELLOWS: Valeria Corti, Giulia Ossato, Antonio Trullo
FELLOW: Moreno Zamai
Mouse functional genetics Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 231
HEAD OF UNIT: Ottavio Cremona*
RESEARCHER: Giuseppina Di Giacomo*
POST-DOCTORAL FELLOWS: Marina Cardano**, Luca Ruggiero**, Elisa Sala**
Clinical Research Units
Clinical and experimental radiology Unit ––––––––––––––––––––––––––––––––––––––––––––––– 232
HEAD OF UNIT: Francesco De Cobelli*
PHYSICIANS: Antonio Esposito*, Claudio Losio, Roberto Nicoletti, Massimo Venturini
225
EXPERIMENTAL IMAGING CENTER
Clinical Research Units/Service Units
High technology in radiation therapy Unit –––––––––––––––––––––––––––––––––––––––––––––– 232
HEAD OF UNIT: Nadia Di Muzio
PHYSICIANS: Genoveffa Berardi, Anna Chiara, Cesare Cozzarini, Italo Dell’Oca, Andrei Fodor,
Paolo Passoni, Najla Slim
RESIDENTS: Barbara Noris Chiorda, Flavia Zerbetto
TECHNICIANS: Alessandro Capelli, Giovannella Salvadori, Andrea Sbalchiero, Simone Selli
Medical physics Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 233
HEAD OF UNIT: Riccardo Calandrino
PHYSICISTS: Sara Broggi, Giovanni Mauro Cattaneo, Antonella Del Vecchio, Claudio Fiorino,
Barbara Longobardi, Paola Mangili, Lucia Perna, Patrizia Signorotto
RESEARCHERS: Giancarmelo Agnello, Maria Luisa Belli, Marco Bianchini, Carmen Gigliotti,
Federica Palorini, Roberta Raso, Carla Sini, Antonello Spinelli
Molecular imaging Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 233
HEAD OF UNIT: Luigi Gianolli
RESEARCHERS: Sara Belloli, Valentino Bettinardi, Assunta Carpinelli, Isabella Castiglioni,
Giuseppe Di Grigoli, Francesca Gallivanone, Maria Carla Gilardi, Elena Incerti, Rosa Maria
Moresco, Maria Picchio, Ornella Rimoldi, Paola Scifo, Silvia Valtorta
PHD STUDENTS: Elena Maria Andreolli, Luca Presotto
PHYSICIANS: Elena Busnardo, Carla Canevari, Federico Fallanca, Claudio Landoni, Patrizia
Magnani, Andrea Panzacchi, Ana Maria Samanes Gajate, Pietro Spagnolo, Paola
Todeschini, Giovanna Vanoli
RADIOCHEMISTS: Valeria Masiello, Maria Grazia Minotti, Cristina Monterisi
TECHNICIANS: Antonia Compierchio, Pasquale Simonelli, Francesco Sudati
Neuroradiology research group ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 234
HEAD OF UNIT: Andrea Falini*
CLINICAL GROUP LEADER: Letterio Salvatore Politi
PHYSICIANS: Simonetta Gerevini, Claudio Righi, Francesco Scomazzoni, Franco Simionato
FELLOWS: Chiara Cianciaruso, Antonella Pagani
Service Units
ALEMBIC, Advanced Light and Electron Microscopy BioImaging Center –––––––– 235
HEAD OF FACILITY: Fabio Grohovaz*
COORDINATORS: Fabio Grohovaz* (Light microscopy); Carlo Tacchetti (Electron microscopy)
RESEARCHER: Maria Carla Panzeri
LAB MANAGER: Andrea Raimondi
TECHNICIANS: Cesare Covino, Andrea Menegon, Desirée Zambroni
Intravital microscopy ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 236
HEAD OF FACILITY: Luca G. Guidotti
RESEARCHERS: Matteo Iannacone, Giovanni Sitia
TECHNICIANS: Tiziana Cataudella, Pietro Di Lucia
EXPERIMENTAL IMAGING CENTER
Service Units
Preclinical MRI and US facility –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 237
HEAD OF UNIT: Antonio Esposito*
PHYSICIANS: Letterio Salvatore Politi, Massimo Venturini
PHYSICIST: Antonello Spinelli
BIOLOGIST: Laura Perani
RESIDENTS: Giulia Agostini**, Giulia Cristel, Paolo Marra**, Anna Palmisano**
TECHNICIANS: Tamara Canu
Pre-clinical PET facility –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 238
HEAD OF FACILITY: Rosa Maria Moresco
RESEARCHERS: Sara Belloli, Paola Scifo
POST-DOCTORAL FELLOWS: Giuseppe Di Grigoli, Silvia Valtorta
FELLOW: Isabella Raccagni
TECHNICIAN: Pasquale Simonelli, Francesco Sudati
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
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EXPERIMENTAL IMAGING CENTER
Introduction by the Directors
Mission and vision - The mission is threefold: 1. Facility - Organizing and providing imaging platforms able
to support independent basic, pre-clinical and clinical research, and to foster translational research in
OSR. 2. Technology development - Continuously developing and providing up-to-date technology through
R&D activities involving biologists, chemists, physicists, computer scientists and clinician scientists. 3.
Research - Hosting independent basic and clinical research groups.
The vision is to create an environment in which the expertise provided by the R&D and research groups
helps the facilities to provide the most up-to-date service possible.
Organization - The Center is composed of 4 Facility Units (Small animal MR and Ultrasound; Small animal PET; Intravital Microscopy; and Light and Electron Microscopy), 3 Basic Research Unit, 5 Clinical
Research Units, for a total of about 70 people. Several members of the CIS are Faculty members of the
Università Vita - Salute San Raffaele.
The Center is also partner of the European Consortium for Nanomedicine, having access to high resolution cryo-EM, EM-tomography and other state-of-the-art EM technologies. The small animal imaging facilities are integrated within the “Mouse Clinic” project in the campus. The Service Units operate on a fee
for service basis for internal and external users.
Finally, due to CIS capabilities and organization, the Light and Electron Microscopy, the pre-clinical MR
and US, and the pre-clinical PET facilities are part of the Italian national nodes of the European Consortium EurobioImaging, a network of facility nodes scattered in Europe.
Goals - (a) foster R&D in Bioimaging; (b) develop research in cardiovascular diseases, oncology, genetic
diseases, metabolic diseases, urology, neurological diseases by mean of Bioimaging; (c) offer technical
and scientific expertise in Bioimaging. The involvement of interdisciplinary competences, including biology, chemistry, physics, informatics and clinical research, will be pivotal to these aims.
Achievements - Significant achievements in all fields of biology, medicine and R&D studied at CIS have
been obtained:
• Clinical and Experimental Radiology: Innovative breast cancer screening program tailored on personal
risk factors. Cardiac MR prospective study of acute myocardial infarction. Development of Diffusionweighted MR technique to characterize lesions and to monitor tumour response to therapy.
• Neuroradiology: Development, optimization and validation of MRI techniques for diagnosis and followup of genetic disease and tumor lesions in pre-clinical models and in clinical applications.
• Molecular Imaging: Clinical research activity using molecular Imaging (SPECT and PET/CT), preclinical
characterization of radiopharmaceuticals, and validation of animal models for different diseases.
• High Technology in Radiation Therapy: Application of Adaptive approach in rectal, head and neck, and
lung cancer. In particular pilot studies are ongoing to: obtain an escalation of tumor dose, for better tumor
regression and low grade side effects in the second half of treatment of rectal cancer; to reduce the
dose to normal tissue in lung and head and neck cancers.
• Medical physics: Development of a preclinical molecular optical imaging Cerenkov method, to image
β+, β-, α and γ emitters. Multimodal imaging acquisition during Radiotherapy treatment to allow the
definition of adaptive strategies to optimize treatment.
• Mouse functional genetics: study of the role of endophilin in mouse genetic.
• Advanced fluorescence microscopy and nanoscopy: Assembly and validation of a new 3D nanoscopy
microscope to study TF/chromatin interaction dynamics.
• Dynamic fluorescence spectroscopy in biomedicine: Set up detection of protein stoichiometry in complexes and optimization of new approaches to analyze time-stack fluorescence multiphoton raster scanning and total internal reflection images.
EXPERIMENTAL IMAGING CENTER
Research Units
Advanced fluorescence microscopy and nanoscopy
research Unit
The behavior of a protein can be determined by
measuring how the protein moves within the intercellular milieu and how it interacts with its partners, or in other words by quantifying its dynamics. Especially in the field of transcription, it is now
demonstrated that different dynamic behaviors of
transcription factors (TFs) are crucial in producing
specific cellular responses to physiological or
pathological stimuli. Unfortunately, the conventional biochemical and microscopical methods
are unable to capture the wide heterogeneity of
dynamical behaviors typically observed for proteins in living cells, underscoring the need for
methods capable of detecting and following single molecules. The microscope can be used to
quantify molecule by molecule kinetic properties
such as the diffusion rates of proteins in living
cells, their binding to other proteins or to immobile
scaffolds (such as the cytoskeleton or chromatin),
and their oligomerization state. Further the capability of the microscope to visualize individual molecules, can be used to overcome the resolution
limit, by applying approaches such as PALM or
dSTORM to obtain fluorescence images with a
spatial resolution below 40 nm (5 times better
then conventional fluorescence microscopy). We
have applied the developed prototype to study
how TFs search for their target sequences on
DNA in living cells, a long-standing question in the
transcription dynamics field. By focusing on the
tumor suppressor p53 we were able to measure
that only a small fraction of the TF is bound
specifically to DNA, and that its binding is very
transient (on the timescale of seconds). Further
our data supports the facilitated diffusion mechanism: when searching for its binding sites p53 first
binds non specifically to DNA by means of its Cterminal tail, and then scans the genome for its
specific targets by means of 1D diffusion. We
have recently extended the microscope to twocolor single-molecule analysis, which has allowed
to identify that p53 binds more strongly to transcriptionally active DNA regions.
Carlo Tacchetti
Figure 39. Two-color
super-resolution
(dSTORM) image
obtained on H1299 lung
carcinoma cells, labelled
with phalloidin-ATTO488
and anti-TubulinAlexa568. Details of
40nm and below can be
resolved in the dSTORM
image.
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EXPERIMENTAL IMAGING CENTER
Research Units
Dynamic fluorescence spectroscopy in biomedicine
Quantitative imaging of protein clustering
We are involved in developing quantitative imaging approaches for elucidating the spatio-temporal dynamics of protein clustering and protein-protein interaction at the cell membrane and in intracellular compartments. Despite the importance
and ubiquity of protein clustering mechanisms in
controlling a variety of cell signaling cascades,
very few methods can be employed for real-time
analysis in live cells. Our approach includes the
combination of phasor-FLIM-FRET and Single
Molecule imaging by the Number of Molecules
and Brightness (N&B) analyses.
By these means, we have uncovered the regulatory role of tetraspanins at the immune synapse
(IS) in live T lymphocytes, by showing that CD81
controls the temporal progression of the IS and
the permanence of CD3 in the membrane contact
area, contributing to sustained T cell receptor
(TCR)-CD3-mediated signaling (Figure 40A).
In a second project, we have addressed the issue
of the fast activation/deactivation of membranebound proteases (MMPs) that are involved in matrix proteins degradation or adhesion receptors
shedding. MMPs display high basal expression but
negligible activity that can be rapidly activated by
unknown mechanisms beyond classical transcriptional or internalization regulation. Different MMPs
associate with tetraspanins, and alterations in
tetraspanin expression levels demonstrate that
tetraspanins are negative regulators of protease
activity. To elucidate the unknown molecular mechanism by which this regulation occurs we are
studying the rapid association/dissociation of
MMPs in tetraspanin-enriched microdomains
(TEM). The combination of phasor-FLIM-FRET and
N&B analysis is unrevealing the stoichiometry of
MMPs homo complexes and their interaction with
TEMs (Figure 40B)
Valeria R. Caiolfa
Figure 40. (A) CD81-mCherry interacts with ICAM-1-mEGFP during conjugation between T cells and
antigen-presenting cells (APCs), and the interaction increases over the time course of IS formation, as
the molecules redistribute throughout the contact area. J77 cells were co-transfected with mEGFPmCherry pairs, conjugated with Raji/SEE cells, and analyzed by phasorFLIM-FRET at the IS, revealing
the area of tight interaction (red mask) between the two proteins. Early IS after 5 min from conjugation;
Late IS after 30 min from conjugation. (Molecular and Cellular Biology, 2013) (B) In migrating cells, the
association of MMPs with TEMs at the basal cell membrane (high FRET eff %) disrupts the MMPs
oligomers (low brightness) (unpublished results).
EXPERIMENTAL IMAGING CENTER
Mouse functional genetics Unit
Mice mutants for endocytosis and neuroferritinopathy
Our research activities have been focused on two
topics:
1. Role of Epsin family members in the function and
homeostasis of human and mouse skin. In recent
years, endocytosis has been characterized as a
major platform for cell signaling activation and regulation. Our laboratory is characterizing the function of a newly family of endocytic adaptors – the
Epsin family – in cell signaling and, possibly, in cancerogenesis. We previously showed that the ubiquitously expressed Epsin1 and Epsin2 are
essential factors for the activation of the Notch signaling pathway during mammalian development.
Currently, we focused on Epsin function in epithelial tissue homeostasis. We found that acute depletion of Epsins by gene knockdown techniques
led to a significant decrease in Notch and Wnt signaling both in vitro and in vivo. These alterations
tightly correlate with subversion of skin differentiation and proliferation and with early endocytic defects in these pathways. Moreover, mice with gene
dosage defects of Epn1 and 2, spontaneously develop pre/paraneoplastic lesions and frankly carcinomatous lesions during aging. These data
strongly suggest an essential role of the Epsin family members in skin homeostasis.
2. Animal models of neuroferritinopathies for the
study of iron in neurodegeneration. Mutations of
ferritin L−chain gene (FTL-1) lead to brain iron accumulation and neurodegeneration in humans. In
collaboration with the S. Levi and F. Grohovaz
Units, we generated and characterized mouse
transgenic mice for a human FTL-1 pathogenic
gene. Transgene expression correlates with increased accumulation of iron and extensive oxidative damage in neurons both in vitro and in vico. The mutated FTL-1 protein showed reduced
capacity to incorporate iron and increased ability
in generating reactive oxygen species. Brain tissues from transgenic mice accumulate lipofuscin
containing iron in GABAergic neurons, as in early
stages of the human disease. Behavioral analyses of mutant mice show motor deficits with a developmental profile of a progressive pathology, as
observed in the human disease. In sum, these
data show that our FTL-1 mice mutants are excellent models to study neuroferritinopathy and may
serve to develop specific therapeutic agents to
target iron dysregulation in brain.
Ottavio Cremona
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EXPERIMENTAL IMAGING CENTER
Clinical Research Units
Clinical and experimental radiology Unit
1. Cardiac Imaging
3. Breast Imaging
a. Myocarditis: in order to find prognostic imaging markers for patients at risk of ventricular
tachyarrhythmias and sudden death.
b. Cardiac CT and MR assessment of structural
substrate of ventricular tachycardia; 3D imaging based modeling of the heart/coronary
anatomy and scars localization as a tool to be
merged with electro-anatomic maps for a
guide of ventricular tachycardia ablation.
c. A cardiac MR-study to evaluate the effect of
GH-deficiency in patients’ heart.
d. Characterization of cardiac masses.
e. Optimization of Cardiac-CT protocols for the
assessment of coronary arteries in re-vascularized patients.
f. Patients with AMI submitted to PCI in order to
evaluate the microvascular obstruction and to
compare our results with coronary angiography and to find new prognostic factors.
a. Two large multicenter studies are ongoing investigating the role of Breast-MRI in two different settings:
• as an alternative tool to mammography and
ultrasound in the screening of women at intermediate risk of breast cancer (MRIB study)
• to demonstrate the performance of MRI over
traditional imaging in the pre-surgical planning of patients diagnosed with breast cancer (MIPA study)
b. Assessment of tumor response in women with
locally-advanced breast cancer undergoing
neoadjuvant chemotherapy.
c. Characterization of breast architectural distortions by means of MRI.
2. Diffusion-weighted MR
5. Interventional Radiology
We aimed to evaluate the accuracy of DWI as a
marker of tumour aggressiveness and tumour response to chemotherapy. We demonstrated the
correlation between ADC and tumour grading factors in prostate, gastroesophageal and rectal cancer and that changes in ADC before and after
neoadjuvant-treatment can be used as reliable
marker of tumor response.
Analysis of innovative therapeutic interventional
approaches for liver metastases, such as a new
TACE using drug eluting beads (DEBIRI technique) and portal embolization for the two-stage
hepatectomy and a study on the extending indications for portal islet autotransplantation after
pancreatic surgery.
Francesco De Cobelli
4. Imaging of islet transplantation
MR functional assessment of micro-vascular
events occurring after pancreatic islets transplantation and relationship with graft outcome.
High technology in radiation therapy Unit
Among its various research project the Radiation
Therapy Dept is collaborating with Nuclear Medicine to define treatment volume on the basis of biological target characteristics, while the last Linac
generation, e.g. Tomotherapy and Rapid Arc permits extreme precision in delivering radiation treatment. The most important result of this combination is improved tumor control with reduced side
effects. In radical treatment of prostate cancer we
obtain 5 year biochemical disease free survival of
100% in Low Risk patients and 97.5% in Intermediate and High Risk patients. In prostate cancer
patients with lymphnodal relapse diagnosed with
Pet choline our radical radiation treatment protocol using high dose to treat the entire lymphnodal
chain with a supplementary boost on Pet positive nodes has resulted in controlled psa and disease in 50% of treated patients after two years
from treatment end. In some cases psa has been
controlled without pharmacological therapy such
as hormonal(HT)or chemotherapy(CT). This result
is important in terms of delaying the use of
drugs(HT or CT)in selected patients for many
years. In rectal cancer treatment using combined
radiochemotherapy with hypofractionated radiotherapy(RT),75% of patients achieved residual tumor cell vitality lower than 5%, as shown in
histopathological examination. It was attempted to
increase the total dose delivered in these patients
by means of the reduction of the treated volume
in the last six sessions of RT administered in
adaptive modality. All patients underwent Diffusion
MR at the start and after ten treatment sessions.
A boost dose to the residual tumor is delivered,
reducing the target volume and the involvement of
the surrounding tissue. This modality allows us to
decrease side effects even with increased total
dose in combination with chemotherapy. Some of
EXPERIMENTAL IMAGING CENTER
these patients refused surgery and are disease
free after 30 months from treatment end. In the
next months the patients will undergo not only Diffusion MR but also FdG PET/TC in order to evaluate the metabolic volume and compare MR and
Pet volume. The ultimate aim of our research in
these rectal cancer patients is to identify a subgroup of patients that can avoid surgery considering that such interventions are frequently demolitive in nature.
Nadia Di Muzio
Medical physics Unit
The main areas of interest of the Medical Physics
Department (MPD) are:
1. Radiotherapy Physics
The main working area of the MPD is the knowledge of advanced methodologies for the optimization of the radiotherapy treatments. Sophisticated treatment units such as tomotherapy and
rapid-arc are continuously monitored and tuned
by the senior staff of the Department. The outcomes were monitored during patients follow up
over several years.
Multi-modal images were acquired before and during the treatment in order to obtain: 1) a more accurate definition of the real extension of neoplastic
disease 2) a better visualization of healthy tissues
3) the evaluation of breathing related tumor/organ
mobility (4D technology) 4) The definition of adaptive strategies to modify treatment plans. A number of studies have been conducted evaluating the
impact of multi-modal approach in treatment planning optimization. Several collaborations with national and international groups have been
consolidated over the last years; two large projects
have been funded by AIRC during the last two
years and are currently in progress.
2. Physics for Imaging
Cerenkov luminescence imaging (CLI) has been
developed by the MPD in collaboration with the
University of Verona and has been applied to
small animals and humans. The MPD also provides support to optical imaging research carried
out at the pre-clinical imaging facility of the centre
for experimental imaging.
A second research topic is the CT dose monitoring and reduction using state of the art iterative reconstruction algorithms.
3. Physics applied to Radioprotection, Laser and
NMR Safety
At OSR is present one of the largest Italian Nuclear Medicine Department (NMD) with two Cyclotrons. The radiation protection of the NMD is
carried out by the MPD with the use of the most
advanced methodologies for radiation monitoring.
Since the beginning of the 80’s the MPD staff is
also enrolled in the safety and quality assurance
of Laser and NMR equipments installed at OSR.
Riccardo Calandrino
Molecular imaging Unit
The main research activities are focused on:
1) Validation of PET/CT with 18F-FAZA for the definition of hypoxia in tumour tissue in patients with
NSCLC. The laboratories are now able to ensure
the quality and safety of the production of the radiopharmaceutical complying with the regulations
in the field of production of radiopharmaceuticals
for diagnostic use. The activities for the implementation of PET laboratories according to Good
Manufacturing Practice (GMP) are also continuing.
2) Preclinical imaging activities for: a) preclinical
evaluation of radioligand for the in vivo imaging of
microglia activation in brain neuroinflammatory
and neurodegenerative disorders; b) combined
use of 18F-FAZA with 18F-FDG or 18F-FLT for
the in vivo characterization of preclinical model of
breast, brain and ovarian cancer; c) evaluation of
the potential use of PET radioligand as biomarkers
of treatment efficacy.
3) In clinical oncological PET studies, the diagnostic accuracy of 18F-FDG and 11C-Choline PET
tracers have been evaluated in several neoplastic
diseases. In particular, in gestational trophoblastic
disease, 18F-FDG PET/CT have been proved to
identify the sites of primary and/or metastatic disease in patients with persistent high levels of
233
EXPERIMENTAL IMAGING CENTER
Clinical Research Units
βHCG after first-line chemotherapy being of additional value in patient management for guiding alternative treatment. The role of 11C-Choline
PET/CT for the detection of prostate recurrent
disease have been demonstrated also at low PSA
serum value, particularly when PSA doubling time
is less than 6 months. This modality may thus be
indicated in the early phases of recurrent disease
to guide personalized treatments.
4) In clinical cardiological studies, 13N-NH3 myocardial blood flow quantification with PET/CT
produced comparable results over different image
reconstruction techniques as well as by using different analysis software programs. The variability
between commercial software programs for the
analysis of cardiac volume and ejection fraction in
13N-NH3 PET/CT were found to be limited. The
prognostic role of SPECT in patients with cardiac
syndrome X and the utility of SPECT for the evaluation of the effect of stem cell transplantation on
cardiac function and perfusion have been
demonstrated.
Luigi Gianolli
Neuroradiology research group
The Neuroradiology Research Group is committed to applying innovative imaging technologies
toward more comprehensive understanding of
pathologies of the central and peripheral nervous
systems at both preclinical and clinical levels, and
to developing new neuro-interventional procedures and protocols for minimally-invasive treatment of neurovascular diseases.
During 2013 the research activity of the Group
was focused on 3 main areas: preclinical studies,
clinical diagnostic research activity and neuro-interventional trials. In the first area, the Group has a
well-established expertise in conventional and advanced MR-based imaging techniques of brain
tumors and of inflammatory, demyelinating and
dysmyelinating murine models of central nervous
system diseases. Using the small-animal 7T MRI
we evaluated and quantified structural changes in
the brains of murine models of several neurological pathologies, such as inherited demyelinating
disorders, stroke and brain tumors. Further, innovative cellular and molecular imaging techniques
were developed for monitoring stem cell transplantation in neurological diseases and for tracking the recruitment of hematopoietic and stromal
cells inside tumors. We explored several cell labeling strategies based on superparamagnetic
iron oxides particles and on different MR-reporter
genes, allowing iron accumulation within cells.
Transgenic mice expressing a mutated form of the
human L-ferritin chain were also analyzed.
In the field of clinical research, the Group worked
on the assessment of structural and functional aspects of brain and orbital inflammatory, infectious
and tumoral disorders. Specific fields of interest
were HIV-related infections and lymphomas. A diffusion tensor imaging study of the cervical spinal
cord was performed on adrenomyeloneuropathy
patients. Additionally, MRI was also applied for
studying hereditary neuromuscular diseases such
as Duchenne muscular dystrophy within a trial
based on mesoangioblast intra-arterial transplantation.
The research in the neuro-interventional area was
focused at the optimization of new endovascular
techniques and at the validation of new angiographic devices for treatment of intracranial
aneurysms, vascular stenosis/occlusions and
artero-venous malformations or shunts.
Letterio Salvatore Politi
EXPERIMENTAL IMAGING CENTER
Service Units
ALEMBIC, Advanced Light and Electron Microscopy
BioImaging Center
The Advanced Light and Electron Microscopy
BioImaging Center, ALEMBIC, has been operating
for more than 10 years at San Raffaele Scientific
Institute as an environment in which biological experimentation requiring optical or electronic imaging is expedited through the ready access to
state-of-the-art instrumentation. Within the facility,
the staff: instructs researchers in the most effective and independent use of microscope setups;
provides continuous support for resolution of scientific problems through the use of the best available technology and correct planning of experi-
mental protocols; promotes technical updates to
keep the facility on the forefront of available technology; performs, when required, full service for
fees.
Alembic aims to stay at the forefront of microscopy innovation to maintain its leadership position in Italy (member of ItaBio) but also in Europe
(member of the EuroBioImaging Italian node).
Thanks to consistent investment by OSR, ALEMBIC is currently undergoing a relevant increase of
its microscopy fleet with the acquisition of new
and important technologies:
Figure 41. Electron microscopy image of the endomebrane system of a primary human plasma cell. (Nu=
Nucleus; GA= Golgi Apparatus; RER= Rough Endoplasmic Reticulum; Cen= Centrosomes. Scale bar 500nm).
Credits: Cenci Lab - Age related diseases Unit
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EXPERIMENTAL IMAGING CENTER
Service Units
• TIRF microscopy, to investigate plasma membrane events
• GSD (Ground State Depletion), a super-resolution approach
• Multiphoton microscopy, for deep imaging living
tissues
• White Light Laser Confocal microscopy with
FLIM-FRET to study protein-protein interactions
These instruments will be available in 2014.
There is also an area in which the staff develops
new methodologies and conducts research on
techniques with significant potential to enhance
bioimaging research. This R&D activity has mainly
converged around the use of voltage sensitive
dyes along two main directions:
• integration of optical recordings with a multi
electrode system to monitor membrane potential changes in neuronal networks (with Politecnico di Milano and San Raffaele Units)
• use in drug discovery screening (patent application n. EP09165872 “Method for optical measuring variations of cell membrane conductance”)
Our numbers for 2013: 821 registered users (331
active), 125 persons attending theoretical/practical courses; ~6000 hours of independent microscopes use; 15 papers spontaneously acknowledging that results were in part enabled by Alembic infrastructures.
Web resources: www.hsr.it/research/alembic
Fabio Grohovaz
Intravital microscopy
Up until few years ago the visualization of cellular
or subcellular processes that control physiological
and/or pathological responses in animal models
has been limited to the static imaging of explanted
tissues. The advent of wide field epifluorescence
single photon intravital microscopy (1P-IVM) and
two photon IVM (2P-IVM) has given us the opportunity to follow those processes within live hosts.
The inability of 1P-IVM to collect images in a “confocal-like fashion” represents both a limitation (narrow image quality as photons are collected also
from out-of-focus planes) and an advantage (fast
speed of acquisition of up to 200 frames/sec)
when compared to 2P-IVM, which has high-resolution and 3-D sectioning capabilities but it usually
acquires a frame every 15-30 sec. Because of
limited surgical access and/or intrinsic anatomical
features, the much more limited depth penetration
of 1P-IVM - as compared to 2P-IVM - restrains
IVM to certain districts (e.g. lymph nodes, spleen,
bone marrow, pancreas, brain, etc) but not others
(e.g. liver, cremaster muscle and various vascular
beds). As such, 1P-IVM represents the best option for studying events that occur rapidly (e.g. cell
adhesion to blood and lymph vessels), while 2PIVM is best suited to follow slow-occurring phenomena (e.g. cell extravasation and cell-cell interaction). Surgical access also imposes the visualization of districts such as the popliteal lymph
nodes, the bone marrow, the cremaster muscle
or the brain with up-right microscopes, while the
visualization of the liver is better performed by the
use of inverted machines. The IVM Facility at OSR
is intended to be a resource for the scientific
community and, at present, it counts on an upright microscope dedicated to 1P-IVM and two
microscopes (one up-right and one inverted) dedicated to 2P-IVM. The facility provides consulting
activity ruling out necessity/feasibility of a given
IVM approach and it is primarily devoted to highly
selected projects that effectively benefit from the
use of this time-consuming and complex technology.
Luca G. Guidotti
EXPERIMENTAL IMAGING CENTER
Preclinical MRI and US facility
Small animal imaging is an integral part of a modern translational
research
Several modalities allow to visualize organs, tissues, or cells, in living animals. Some imaging
modalities are exclusive for preclinical imaging, as
the optical imaging, instead most of them are the
same applied in the clinical setting. The Preclinical
MRI and US Facility is equipped with a 7T Magnetic Resonance scanner (Bruker; BioSpec
70/30), a dedicated Ultrasound scanner (Vevo
2100; Visualsonic) and a combined Optical Computed Tomography scanner (IVIS SpectrumCT® Perkin Elmer), therefore as the capability to
offer tailored assistance to researchers needing to
characterize their small animal models or to perform longitudinal imaging studies.
All the modalities are non-invasive and are managed with the scientific collaboration of imaging
experts, which may propose the best imaging
protocol for each specific task:
Antonio Esposito (Head of the Facility and Coordinator of body-MRI);
Letterio Salvatore Politi (Coordinator of neuroMRI);
Massimo Venturini (Coordinator of US);
Antonello Spinelli (Coordinator of Optical Imaging).
In 2013 the Facility collaborated with both internal
and external researchers on several issues:
• MRI monitoring of acute and chronic muscle injury and regeneration
• MRI monitoring of liver neoplastic burden (both
HCC and metastasis)
• MRI staging of disease in mice genetically predisposed to develop pancreatic cancer
• MRI and US monitoring of disease burden in
mouse models of polycystic kidney disease
• MRI and US monitoring transgenic models of
prostate cancer
• MRI and US monitoring of lymphedema after
lymph-node dissection and transplantation
• MRI and CT characterization of a mouse model
of osteoarthritis
• In-vivo and ex-vivo MRI assessment of atherosclerotic burden and plaques instability
• MRI of cerebral ischemic stroke models
• MRI characterization of mouse models of neuroferritinopathies
• MRI study on specificity of SPIO signal for cellular imaging purposes
• In vivo MRI monitoring of SPIO labeled leukocytes migration into nodules of peritoneal carcinogenesis
• Brain and spinal MRI in mouse models of multiple sclerosis
• US monitoring of models of peritoneal carcinogenesis
• US assessment of splenomegaly in Wiscott
Aldrich syndrome models
• US assessment of leukemic mice
• Preliminary experience of US guided punctures
in mice.
Antonio Esposito
Figure 42. Collection of images obtained with the 7T MRI scanner: On the left coronal color coded map of a
Diffusion Tensor Imaging study performed on mouse brain; each color represent the preferential direction white
matter fibers.
In the center the diastolic frame of a long axis cine view of the mouse heart; are clearly depicted the left
and right ventricles and the aortic valve with ascending aorta and aortic arch.
On the right a 3D reconstruction of the liver of a mouse model of chronic hepatitis B; in transparent lightgreen is represented the normal liver parenchyma and in dark-green are segmented the HCC nodules.
237
EXPERIMENTAL IMAGING CENTER
Service Units
Pre-clinical PET facility
The Laboratory of Preclinical PET Imaging, localized within the Nuclear Medicine Department of
the San Raffaele Hospital, operates and has access through formal collaborations with personnel
and instrumentation installed inside the laboratory
belonging to the Institute of Bioimaging and Molecular Physiology (IBFM) of the National Research
Council and the Tecnomed Foundation of University of Milan Bicocca. Imaging studies are performed taken advantage of the single photon or
positron emitters labeled radiopharmaceuticals
developed by the laboratory Radiochemistry of
the Nuclear Medicine Department.
Main activities of the laboratory are focused on the
use of emission tomography techniques for: a)
characterization of kinetics and biological properties of novel radiopharmaceuticals; b) characterization of preclinical model of diseases using
emission tomography techniques in comparison of
the different clinical presentation of patients evaluated with PET or SPECT in clinical practice as well
as during research protocols; c) design and set up
of preclinical imaging studies for drug the characterization of novel therapeutic strategies.
Studies are performed on animal or cellular model
prepared by other research groups or directly by
the personnel of the laboratory. Radiopharmaceutical development includes the characterization and
measurement of the circulating and tissue fraction
of radiolabeled metabolites and the evaluation of
the potential diagnostic sensitivity of the probes
using adequate animal model of diseases.
The laboratory is equipped with:
• Small animal dedicated PET/SPECT tomograph
• Equipment for administration of volatile anesthetic
• Phosphor-imager for authoradiography
• HPLC system for the analysis of radiolabeled
metabolites
• Gamma counter
• Cryostat for tissue dissection
• Stereotaxic surgery apparatus for mice and rats
• Work stations e software for image analysis and
quantification
The laboratory is also equipped with ventilated
cabinet for animal housing authorized by local and
national institutions and is connected with the general facility for animal housing and care.
Rosa Maria Moresco
EXPERIMENTAL IMAGING CENTER
Selected publications
Cattaneo, GM; Passoni, P; Longobardi, B; Slim, N; Reni, M; Cereda, S; Di Muzio, N; Calandrino, R. Dosimetric and clinical predictors of toxicity following combined chemotherapy and moderately hypofractionated rotational radiotherapy of locally advanced pancreatic adenocarcinoma. Radiother. Oncol.: 2013; 108(1): 66-71 - Article
IF 2012: 4,520
Fellin, F; Azzeroni, R; Maggio, A; Lorentini, S; Cozzarini, C; Di Muzio, N; Fiorino, C; Calandrino,
R; Schwarz, M. Helical tomotherapy and intensity modulated proton therapy in the treatment of
dominant intraprostatic lesion: A treament planning comparison. Radiother. Oncol.: 2013; 107(2):
207-212 - Article
IF 2012: 4,520
Sitia, G; Iannacone, M; Guidotti, LG. Anti-platelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma. J. Hepatol.: 2013; 59(5): 1135-1138 - Article
IF 2012: 9,858
Trullo, A; Corti, V; Arza, E; Caiolfa, VR; Zamai, M. Application limits and data correction in number
of molecules and brightness analysis. Microsc. Res. Tech.: 2013; 76(11): 1135-1146 - Article
IF 2012: 1,593
Mazza, D; Mueller, F; Stasevich, TJ; McNally, JG. Convergence of chromatin binding estimates in
live cells. Nat. Methods: 2013; 10(8): 691-692 - Letter
IF 2012: 23,565
Cortese, K; Howes, MT; Lundmark, R; Tagliatti, E; Bagnato, P; Petrelli, A; Bono, M; McMahon, HT;
Parton, RG; Tacchetti, C. The HSP90 inhibitor geldanamycin perturbs endosomal structure and
drives recycling ErbB2 and transferrin to modified MVBs/lysosomal compartments. Mol. Biol. Cell.:
2013; 24(2): 129-144 - Article
IF 2012: 4,803
Spinelli, AE; Ferdeghini, M; Cavedon, C; Zivelonghi, E; Calandrino, R; Fenzi, A; Sbarbati, A;
Boschi, F. First human Cerenkography. J. Biomed. Opt.: 2013; 18(2): 20502 - Letter
IF 2012: 2,881
Zonari, E; Pucci, F; Saini, M; Mazzieri, R; Politi, LS; Gentner, B; Naldini, L. A role for miR-155 in
enabling tumor-infiltrating innate immune cells to mount effective antitumor responses in mice.
Blood: 2013; 122(2): 243-252 - Article
IF 2012: 9,060
Venturini, E; Losio, C; Panizza, P; Rodighiero, MG; Fedele, I; Tacchini, S; Schiani, E; Ravelli, S;
Cristel, G; Panzeri, MM; De Cobelli, F; Del Maschio, A. Tailored breast cancer screening program with microdose mammography, us, and mr imaging : Short-term results of a pilot study in 4049-year-old wome. Radiology: 2013; 268(2): 347-355 - Article
IF 2012: 6,339
Esposito, A and Campana, L; Palmisano, A; De Cobelli, F; Canu, T; Santarella, F; Colantoni,
C; Monno, A; Vezzoli, M; Pezzetti, G; Manfredi, AA; Rovere-Querini, P; Del Maschio, A. Magnetic Resonance Imaging at 7T Reveals Common Events in Age-Related Sarcopenia and in the
Homeostatic Response to Muscle Sterile Injury. PLoS ONE: 2013; 8(3): e59308 - Article
IF 2012: 3,730
De Cobelli, F; Giganti, F; Orsenigo, E; Cellina, M; Esposito, A; Agostini, G; Albarello, L; Mazza,
E; Ambrosi, A; Socci, C; Staudacher, C; Del Maschio, A. Apparent diffusion coefficient modifications in assessing gastro-oesophageal cancer response to neoadjuvant treatment: comparison with
tumour regression grade at histology. Eur. Radiol.: 2013; 23(8): 2165-2174 - Article
IF 2012: 3,548
Passoni, P; Reni, M; Cattaneo, GM; Slim, N; Cereda, S; Balzano, G; Castoldi, R; Longobardi,
B; Bettinardi, V; Gianolli, L; Gusmini, S; Staudacher, C; Calandrino, R; Di Muzio, N. Hypofractionated image-guided IMRT in advanced pancreatic cancer with simultaneous integrated boost to
infiltrated vessels concomitant with capecitabine: A phase i study. Int. J. Radiat. Oncol. Biol. Phys.:
2013; 87(5): 1000-1006 - Article
IF 2012: 4,524
Picchio, M; Piert, M. Prostate cancer imaging. Eur. J. Nucl. Med. Mol. Imaging: 2013; 40(Suppl 1):
S1-S4 - Editorial
IF 2012: 5,114
239
EXPERIMENTAL IMAGING CENTER
Selected publications
Garibotto, V; Tettamanti, M; Marcone, A; Florea, I; Panzacchi, A; Moresco, R; Virta, JR; Rinne, J;
Cappa, SF; Perani, D. Cholinergic activity correlates with reserve proxies in Alzheimer’s disease.
Neurobiol. Aging: 2013; 34(11): e13-e18 - Article
IF 2012: 6,166
Esposito, A; Colantoni, C; De Cobelli, F; Del Vecchio, A; Palmisano, A; Calandrino, R; Del
Maschio, A. Multidetector computed tomography for coronary stents imaging: High-voltage (140KVP) prospective ecg-triggered versus standard-voltage (120-kvp) retrospective ecg-gated helical
scanning. J. Comput. Assisted Tomogr.: 2013; 37(3): 395-401 - Article
IF 2012: 1,582
EXPERIMENTAL IMAGING CENTER
ALEMBIC
Dynamic fluorescence spectroscopy in biomedicine
241
RESEARCH
PROGRAMMES
Brain Regeneration usIng medical Devices, Gene vectors and stEm cells (BRIDGE)
Head of Research Program:
Gianvito Martino (ad interim)
Deputy Head of Research Program:
Luigi Naldini*
Participating investigators:
Alessandra Biffi, HSR-TIGET - The San Raffaele Telethon Institute for Gene Therapy
Alessandra Bolino, INSPE - Institute of Experimental Neurology
Vania Broccoli, Division of Neuroscience
Gian Giacomo Consalez, Division of Neuroscience
Roberto Furlan, INSPE - Institute of Experimental Neurology
Rossella Galli, Division of Regenerative medicine, Stem cells, and Gene therapy
Angela Gritti, HSR-TIGET - The San Raffaele Telethon Institute for Gene Therapy
Letizia Leocani, INSPE - Institute of Experimental Neurology
Gianvito Martino, INSPE - Institute of Experimental Neurology
Pietro Mortini, Division of Neuroscience
Luigi Naldini, HSR-TIGET - The San Raffaele Telethon Institute for Gene Therapy
Stefano Pluchino, INSPE - Institute of Experimental Neurology
Letterio Salvatore Politi, Experimental Imaging Center
Stefano Carlo Previtali, INSPE - Institute of Experimental Neurology
Angelo Quattrini, INSPE - Institute of Experimental Neurology
Carla Taveggia, INSPE - Institute of Experimental Neurology
Flavia Valtorta, Division of Neuroscience
243
RESEARCH PROGRAMMES
Vision - The characterization, dissection and experimental manipulation of the molecular and cellular events sustaining reactive brain repair might
provide an attractive conceptual framework to
foresee more efficacious therapies for neurological diseases. Indeed, fostering and/or resetting
‘spontaneous’ neural tissue regenerative processes may lead to ‘natural’ therapies characterized by
higher efficacy and less toxicity. As a matter of
fact, sspontaneous neural tissue repair occurs in
patients affected by inflammatory and degenerative disorders of the nervous system. However,
this process is not robust enough to promote a
functional and stable recovery of the 3D neural
tissue architecture. The development of stem celland gene therapy-based approaches capable of
promoting the restoration and/or regeneration of
the diseased or injured nervous system is thus
foreseeable.
Goals - Experimental strategies aiming at either
replacing damaged vs. injured neural cells or delivering therapeutic genes have been developed
in the last 30 years. However, most of these experimental approaches have failed to consistently
foster repair in multifocal neurological diseases
where the anatomical and functional damage is
widespread. Novel stem cell- and gene therapybased protocols might partially overcome some of
these limitations, including (a) the poor capability
to grow and differentiate in vitro large number of
neural cells from progenitors; (b) the anatomical,
immunological and ethical barriers to cell transplantation into the CNS; (c) the limited bio-distribution of gene transfer products to the neural tis-
sues, as well as (d) the genotoxic and immunological risks associated with conventional cell and
gene delivery approaches. Novel therapeutic approaches that overcome these important hurdles
might therefore represent valid alternatives for the
treatment of multifocal nervous system diseases.
These novel approaches may be complemented
by the development of biocompatible medical devices providing the appropriate microenvironment
to foster functional integration of the transplanted
or endogenous gene-modified cells into the damaged tissues.
Main achievements - The program has capitalized the scientific expertise and clinical excellence
available at OSR in the areas of interest. Premiere
knowledge derived from state-of-the-art stem cell
and gene therapy experimental and human trials
conducted in our Institute for a number of inflammatory and neurodegenerative conditions has
been further expanded. New phase I/II human trials have been initiated in different myelin disorders, including multiple sclerosis and leukodystrophies, and new therapeutic pre-clinical strategies
have been further developed in relevant animal
model of neurodegenerative diseases. All of this
work has been conducted with the main aim of
combining powerful new stem cell isolation and
gene transfer approaches to state-of-the-art neuroimaging, immunological and neurophysiological
readouts. Finally, biological models has been developed to allow tracking gene expression and
neural activity in the transplanted cells and the
treated tissues.
RESEARCH PROGRAMMES
Program in Immunology and Bio-immunotherapy of
Cancer (PIBIC)
Co-Heads of Research Program:
Paolo Dellabona and Giorgio Parmiani
Participating investigators:
Matteo Bellone, Division of Immunology, Transplantation, and Infectious Diseases
Chiara Bonini, Division of Regenerative medicine, Stem cells, and Gene therapy
Giulia Casorati, Division of Immunology, Transplantation, and Infectious Diseases
Angelo Corti, Division of Molecular oncology
Paolo Dellabona, Division of Immunology, Transplantation, and Infectious Diseases
Angelo A. Manfredi, Division of Regenerative medicine, Stem cells, and Gene therapy
Anna Mondino, Division of Immunology, Transplantation, and Infectious Diseases
Giorgio Parmiani, Division of Molecular oncology
Maria Pia Protti, Division of Immunology, Transplantation, and Infectious Diseases
Patrizia Rovere-Querini, Division of Regenerative medicine, Stem cells, and Gene therapy
Vincenzo Russo, Division of Molecular oncology
Vision - The Program in Immunology and Bio-Immunotherapy of Cancer (PIBIC) combines expertise in immunology, cancer biology and medical
onco-hematology to investigate fundamental aspects of tumor immunology and translate them into innovative immunotherapy strategies for phase
I/II clinical trials.
Goals - PIBIC aims at: a) gaining a deeper under-
standing of the mechanisms underlying the tumor/immune system interactions; b) providing rationally designed immunotherapy strategies that
may significantly increase the clinical response.
Main achievements - The immunogenicity of somatically mutated antigens in colon cancer was
demonstrated by massive sequencing of the cancer transcriptome and reverse immunology (P.
245
RESEARCH PROGRAMMES
Dellabona, G. Parmiani). We also obtained evidence that T cells specific for CD1c-restricted
methylated lyso-phospholipid antigens can control leukemia progression (G. Casorati).
New mechanisms of immunosuppression in the
tumor microenvironment were defined: a) inhibition of antitumor immune responses by tumor-derived oxysterols via recruiting pro-tumor neutrophils in the tumor microenvironment (V. Russo);
b) frequency of bone marrow pro-tumor Th22
cells greater in multiple myeloma patients with
poor prognosis than low-risk patients and healthy
controls (M.P. Protti). Studies focusing on targeting angiogenesis and tumor-microenvironment
demonstrated the efficacy of delivering TNF and
other cytokines to tumors via peptide-tagged
nanoparticles capable of homing to tumor vessels. Chromogranin A was also found to act as
angiogenic switch activated by proteolytic cleavage in damaged tissues and in tumors (A. Corti).
Improvement of immunotherapy strategies was also obtained: booster vaccinations with a tumorspecific vaccine were detrimental in tumor-bearing subjects because of the negative impact on
central memory T cells (M. Bellone). Remarkable
control of a realistic mouse prostate cancer model was achieved by adoptive T cell therapy with T
cells redirected against tumor and stroma by TCR
gene transfer, or by combining tumor-redirected T
cells with tumor-targeted NGR-TNF (A. Mondino).
Significant advancements in adoptive T cell therapy were obtained: a) with CAR-engineered human T cells by developing a new chimeric antigen
receptor specific for the CD44v6 isoform to target
acute myeloid leukemia and multiple myeloma (A.
Bondanza); b) by defining conditions to generate
and expand long-lived human memory stem T
cells for adoptive cell therapy by IL-7 and IL-15
(C. Bonini).
The characterization of cancer stem cells (CSC)
as targets for immunotherapy defined gene expression signatures of mouse stage-specific
prostate CSC lines that associated with subgroups of progressing prostate cancer patients
(M. Bellone). The suppressive mechanisms of human colorectal CSC were found to depend on indolamine 2,3-dioxigenase and/or on increased
expression of cell surface IL-4 (G. Parmiani).
New clinical trials that incorporate the conceptual
advancements conceived within PIBIC were conducted:
• A new strategy of vaccination by loading dendritic cells with tumor antigens in vivo was applied to 23 MAGE-A3+ stage IIIC or IV
melanoma patients by transferring autologous
lymphocytes engineered with MAGE-A3 and
HSV-TK. Disease control rate of 26.3% (1 CR, 4
SD) and positive correlation between the increase of MAGE-A3-specific effectors and
overall survival was observed in 19 patients with
measurable disease.
• A protocol based on the combination of NGRhTNF and peptide vaccine was conducted on 8
metastatic melanoma patients. Immune response to the vaccine and to other melanoma
antigens, partly associated with the clinical outcome, and OS close to 30 months in 4 subjects were found (G. Parmiani).
• -A phase I study combining Ipilimumab and
Fotemustine in metastatic melanoma was performed in 19 patients. The treatment induced
PRs of brain metastases in 50% of patients. A
phase III protocol is now ongoing (G. Parmiani).
RESEARCH PROGRAMMES
Islet Trasplantation Program (ITP)
Co-Heads of Research Program:
Lorenzo Piemonti and Paola Maffi
Participating investigators:
Manuela Battaglia, DRI - Diabetes Research Institute
Luca G. Guidotti, Division of Immunology, Transplantation, and Infectious Diseases
Emanuele Bosi, DRI - Diabetes Research Institute; Division of Metabolic and Cardiovascular sciences
Paola Maffi, DRI - Diabetes Research Institute
Rita Nano, DRI - Diabetes Research Institute
Marina Scavini, DRI - Diabetes Research Institute
Vision - The mission of this program is to achieve
long-lasting insulin independence in patients with
type 1 diabetes (T1D) undergoing portal vein islet
transplantation. Recognized experts in islet transplantation, immunological tolerance, liver immunopathology and non-invasive imaging have
been brought together to address and modify innate and adaptive immune responses to islet
transplants that together prevent lifelong persistence of functional islets within the liver.
Goals - Aims of this program are:
1) to improve donor management, donor selection criteria, organ recovery techniques and
islet cell processing techniques. Expected results: identification of more efficient islet cell
processing to maximize islet recovery;
2) to identify and standardize methods for the
evaluation of islet preparations intended for
transplantation in humans (i.e. cell composition,
cell viability, insulin secretion). Expected results:
identification and validation of predictor for islet
engraftment and post transplant function;
3) to identify strategies and drugs able to improve
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RESEARCH PROGRAMMES
islet “engraftment”. Expected results: achieve
successful islet transplantation from one donor
to one recipient;
4) to develop single or multi centre clinical trial to
test new immunosuppression and tolerogenic
strategies. Expected results: achieve successful islet transplantation without immunosuppression or with less toxic immunosuppressive
regimens;
5) to provide islets for researchers. Expected results: support research activity related to cell
biology in Europe.
Main achievements - During the last year we:
• have implemented a calcineurin inhibitor-free,
anti-IL-2R-free protocol to clinical islet transplantation (NCT01346085). This “tolerance-accommodating” protocol resulted feasible, safe
and efficient in term of maintaining patients insulin-free at 3 years;
• demonstrate that immune monitoring with frequent posttransplant assessment of allo- and
autoantibodies could be helpful in clinical islet
transplantation. This approach to active immune
monitoring should allow for the use of more-tailored (and potentially milder) immunosuppression combinations and prompt intervention for
acute immunological events. In addition, such
monitoring may provide a better understanding
and characterization of the various mechanisms
of destruction involved in the loss of islet grafts;
• performed the first clinical study aiming to investigate in noninvasive way liver perfusion modifications occurring during islet engraftment and
attempting to correlate them with clinical parameters in T1DM patients. Dynamic contrast-enhanced magnetic resonance imaging (DCEMRI) identifies various adaptive responses of liver microvasculature in patients submitted to islet
transplantation; these responses could have an
impact on islet engraftment;
• conducted a phase 3, multicenter, randomized,
double-blind, parallel assignment study to assess the efficacy and safety of the CXCR1/2 inhibitor reparixin in pancreatic islet transplantation
(NCT01817959);
• conducted a phase 2 study to compare bone
marrow vs. liver as site for islet transplantation in
patients (NCT01722682);
• extended the clinical indication of islet autotransplantation to a broader population of patients undergoing pancreatic surgery including
subjects with technically unfeasible or high risk
pancreatic anastomosis during partial pancreatectomy and subjects undergoing completion
pancreatectomy because of anastomosis leakage after pancreatoduodenectomy for nonmalignant or malignant diseases (NCT01702051).
RESEARCH PROGRAMMES
Human Brain Invivo Mapping with neuroimaging
(BRAINMAP)
Head of Research Program:
Massimo Filippi*
Deputy Head of Research Program:
Andrea Falini*
Participating investigators:
Francesco Benedetti, Division of Neuroscience
Luigi Beretta, Division of Neuroscience
Stefano F. Cappa, Division of Neuroscience
Paola Cinque, Division of Immunology, Transplantation, and Infectious Diseases
Andrea Falini, Division of Neuroscience
Massimo Filippi, INSPE - Institute of Experimental Neurology
Roberto Gatti, Division of Neuroscience
Letizia Leocani, INSPE - Institute of Experimental Neurology
Giuseppe Magnani, INSPE - Institute of Experimental Neurology
Vittorio Martinelli, INSPE - Institute of Experimental Neurology
Daniela Perani, Division of Neuroscience
Maria Assunta Rocca, INSPE - Institute of Experimental Neurology
Maria Sessa, INSPE - Institute of Experimental Neurology
249
RESEARCH PROGRAMMES
Vision - Due to its exquisite sensitivity, relative
non-invasiveness, and major technical advances,
neuroimaging has become in the past couple of
decades an irreplaceable way for the in vivo assessment of the CNS in healthy and diseased humans.
Goals - The “Human Brain In-vivo Mapping with
Neuroimaging” (BRAINMAP) Research Program is
aimed at joining and strengthening the decennial
neuroimaging expertise developed at our Institute;
and developing new research lines through a multidisciplinary and inter-departmental approach.
Main achievements
• MS and other WM disorders: imaging features
of cortical lesions and cervical cord atrophy
were assessed in patients with different MS
phenotypes; advanced MRI techniques identified predictors of cognitive and clinical deterioration in MS; the role of brain and cognitive reserves in limiting onset of cognitive deficits in
MS was demonstrated; in pediatric MS, structural and functional MRI improved the understanding of the correlates of cognitive impairment; GM regional abnormalities were explored
in adult and pediatric migraine.
• Neurodegenerative diseases: DT MRI revealed
specific patterns of WM damage in patients with
early onset AD, primary progressive aphasia,
PD, and MND; resting state fMRI abnormalities
were assessed in FTD and MND; graph analysis showed that global and local functional networks are altered in FTD; social cognition impairment were assessed in the FTD spectrum
as well as their relationship with GM and WM
damage.
• Psychiatric diseases: the GSK-3 inhibitor lithium, and the less active GSK-3 gene promoter
variants, add on to counteract the detrimental
effects of bipolar disorder on WM; widespread
WM changes are common to obsessive-compulsive disorder, and a target for drug treatment;
fMRI reveals gene-environment interactions between COMT genotype and the neural correlates of empathy and perceived personal dis-
tress in schizophrenia.
• Infectious diseases: DT MRI revealed WM abnormalities in patients with asymptomatic HIV infection, including treated chronic infection representing a potential marker to study cognitive
deficits in this population; in PML, MRI enhancement patterns and evolution is being
studied in the context of the relationship between JC virus replication and host response
providing a useful means for clinical disease
monitoring.
• Developmental disorders: Voxel-basedmorphometry and DT MRI were applied in subjects with sporadic dyslexia and genetic association, subjects with DCDC2 mutation associated with altered neuronal migration and cognitive
disturbances, providing evidence for structural
alterations of neural systems supporting reading
and specific cognitive processes.
• Clinical neuroscience: psycholinguistic, neuropsychological and neuroimaging studies of
abstract word processing in normal subjects;
assessment of the functional and structural correlates of loss of aversion in normal subjects, including the investigation of individual differences; functional correlates of innovative decision-making in managers and entrepreneurs.
• Neurophysiological techniques: using advanced
source localization of cognitive event-related
potentials to the Stroop test, the electrophysiological and psychophysiological correlates (reaction times) of frontal executive involvement
were explored in MND.
• Nuclear medicine techniques: the amyloid load
was assessed using PET and fluorinated tracers
in MCI/prodromal AD and compared with FDG
PET functional derangement, supporting divergent pathways for these biomarkers that might
guide clinical applications; the mechanisms of
neuroinflammation were explored using 11CPK-PET in PD and parkinsonisms, AD and prion
diseases; FDG PET scans in patients with neurodegenerative disorders were evaluated providing brain functional, clinical and neuropsychological correlations useful for research purposes and clinical applications.
RESEARCH PROGRAMMES
Figure 43. Graph analysis of resting state functional MRI in patients with the behavioural variant of frontotemporal
dementia (bvFTD). (A) Cortical hubs of the functional networks of healthy controls (i, ii) and patients with bvFTD (iii,
iv). (B) Regions showing decreased integrated nodal degree (i, ii) in patients with bvFTD compared to healthy
controls. Node size is proportional to the difference in the value of the integrated nodal parameters between the 2
groups. Abbreviations: ACC = anterior cingulate cortex; Cal = calcarine cortex; Caud = caudate nucleus; Cun =
cuneus; Fus = fusiform gyrus; Hes = Heschl gyrus; Ins = insula; IOG = inferior occipital gyrus; ITG = inferior
temporal gyrus; Lin = lingual gyrus; MCC = middle cingulate cortex; MFG = middle frontal gyrus; MOG = middle
occipital gyrus; MTG = middle temporal gyrus; OFC = orbitofrontal cortex; Prec = precuneus; PoCG = postcentral
gyrus; PreCG = precentral gyrus; Rec = gyrus rectus; Rol = rolandic operculum; SFG = superior frontal gyrus;
SOG = superior occipital gyrus; SPL = superior parietal lobule; STG = superior temporal gyrus; TPO = temporal
pole. Reproduced with permission from Agosta F, Sala S, Valsasina P, Meani A, Canu E, Magnani G, Cappa SF,
Scola E, Quatto P, Horsfield MA, Falini A, Comi G, Filippi M. Brain network connectivity assessed using graph
theory in frontotemporal dementia. Neurology 2013;81:134-43.
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RESEARCH PROGRAMMES
Bone Physiopathology Program (BoNetwork)
Co-Heads of Research Program:
Roberto Sitia* and Enrico Gherlone*
Participating investigators:
Alessandra Biffi, HSR-TIGET - The San Raffaele Telethon Institute for Gene Therapy
Clara Camaschella, Division of Genetics and Cell biology
Francesco Camnasio, Department of general and specialistic surgery
Simone Cenci, Division of Genetics and Cell biology
Roberto Crespi, Division of Genetics and Cell biology
Marina Ferrarini, Division of Molecular oncology
Elisabetta Ferrero, Division of Molecular oncology
Gianfranco Fraschini, Division of Genetics and Cell biology
Federico Furlan, Emergency medicine
Roberto Gatti, Division of Neuroscience
Enrico Gherlone, Division of Genetics and Cell biology
Stefano Mora, Division of metabolic and cardiovascular sciences
Giuseppe M. Peretti, Division of Genetics and Cell biology
Patrizia Rovere-Querini, Division of Regenerative medicine, Stem cells, and Gene therapy
Alessandro Rubinacci, Division of metabolic and cardiovascular sciences
Roberto Sitia, Division of Genetics and Cell biology
Giovanni Tonon, Division of Molecular oncology
Giuseppe Vezzoli, Division of Genetics and Cell biology
Anna Villa, HSR-TIGET - The San Raffaele Telethon Institute for Gene Therapy
Raffaele Vinci, Division of Genetics and Cell biology
RESEARCH PROGRAMMES
Vision - The skeleton evolved to empower locomotion, shield the neuraxis and the hematopoietic
marrow, and amass minerals. Efficient mechanosensing ensures skeletal homeostasis by co-ordinating the remodeling activity of bone-forming osteoblasts and bone-resorbing osteoclasts. Bone
metabolic diseases are frequent and disabling: involutional osteoporosis affects older people (35%
postmenopausal white women, 19% white men),
leading to pathologic fractures (>1.3 million/year),
high costs (14 billion USD direct expenditures per
year in the US), severe disability, and reduced
lifespan. These figures rise as life expectancy
grows, warranting new strategies to promote
healthy aging.
Understanding how osteoblasts and osteoclasts
differentiate and operate, their derangement in
bone wasting diseases, and how cancers divert
the bone microenvironment will provide targets for
osteoporosis and osteolytic cancers. The integrated study of bone biology, stemness, and immunity will expand our understanding of skeletal
homeostasis, and lead to identify new specific
therapeutic targets for regenerative medicine.
Goals - The San Raffaele Bone Pathophysiology
Program (BoNetwork) aims to integrate basic,
translational and clinical research on bone pathophysiology to generate strong scientific synergies.
Specific objectives include: identifying the molecular and cellular bases of bone homeostasis, including determinants of bone mass gain; promoting joint efforts in cartilage and bone engineering
in orthopaedics and odontoiatrics; identifying po-
tential molecular markers and targets of diseases;
establishing robust cellular and animal disease
models, and solid core technologies; providing an
attractive interface for pharmaceutical and nutriceutical companies.
Main recent achievements
• Development and preclinical validation of strategies for cartilage and osteochondral repair, including: an engineered osteochondral composite; human cartilage fragments as a cell source;
fibrin glue and collagen scaffold as a carrier;
• Development of animal models of skeletal aging
and to develop tissue engineering strategies for
articular repair;
• Evaluation of the effects of chronic diseases
and associated treatments (HIV and antiretrovirals) on skeletal modeling in children/adolescents;
• Identification of genetic variants associated with
osteoporosis;
• Identification of mechanisms conferring therapeutic resistance to multiple myeloma, the
prime bone cancer;
• Discovery of the role of autophagy in plasma
cell ontogenesis and in the maintenance of the
resident pool of bone marrow plasma cells, the
normal myeloma counterpart;
• Identification and characterization of gene variants of the calcium-sensing receptor associated with human disease;
• Studies of biological features and clinical applications of bone substitutes and dental implants
for oral rehabilitation.
253
RESEARCH PROGRAMMES
Correlates of HIV-Associated Immune Response Modulation program (CHARM)
Co-Heads of Research Program:
Paola Cinque and Guido Poli*
Participating investigators:
Massimo Alfano, Division of Immunology, Transplantation, and Infectious Diseases
Antonella Castagna, Division of Immunology, Transplantation, and Infectious Diseases
Paola Cinque, Division of Immunology, Transplantation, and Infectious Diseases
Nicola Gianotti, Division of Immunology, Transplantation, and Infectious Diseases
Luca G. Guidotti, Division of Immunology, Transplantation, and Infectious Diseases
Adriano Lazzarin, Division of Immunology, Transplantation, and Infectious Diseases
Mauro S. Malnati, Division of Immunology, Transplantation, and Infectious Diseases
Giulia Morsica, Division of Immunology, Transplantation, and Infectious Diseases
Ruggero Pardi, Division of Immunology, Transplantation, and Infectious Diseases
Guido Poli, Division of Immunology, Transplantation, and Infectious Diseases
Gabriella Scarlatti, Division of Immunology, Transplantation, and Infectious Diseases
Giuseppe Tambussi, Division of Immunology, Transplantation, and Infectious Diseases
Caterina Uberti-Foppa, Division of Immunology, Transplantation, and Infectious Diseases
Luca Vangelista, Division of Immunology, Transplantation, and Infectious Diseases
Elisa Vicenzi, Division of Immunology, Transplantation, and Infectious Diseases
Vision - After the discovery of HIV-1 as the cause
of AIDS (1983-1984), CD4 was soon identified as
the primary receptor utilized by the virus to infect T
lymphocytes and mononuclear phagocytes.
However, 10 years passed before the identification of the second co-receptor required for viral
entry in the molecule known as CCR5. Genetic
variants of CCR5 include a deletion of 32 base
pairs leading to misfolding of the protein and lack
of surface expression. Individuals who are homozygotes for such a mutation are naturally resistant to HIV-1 infection, whereas heterozygotes
RESEARCH PROGRAMMES
are frequently “long-term nonprogressors”, thus
underscoring the importance of this receptor in
the natural history of HIV-1 infection.
CCR5 binds to 3 natural CC chemokines and
these observations have led to the rapid discovery of small molecules antagonizing HIV infection
at the entry step. CCR5 antagonists are indeed
the first drugs approved for their use in regimens
of combination anti-retroviral therapy (cART) of
HIV-1 infection that are targeting a host rather than
a viral protein. The specific clinical use of CCR5
antagonists in the context of potent cART might
be significantly enhanced by their potential “immunomodulatory/anti-inflammatory” effect resulting from the interference with the chemokine receptor. If proven, this activity could be exploited in
other clinical conditions where reduction of the inflammatory cell state by interference with CCR5
could be desirable.
Goals - General goals of CHARM are the investigation and exploitation of the role of CCR5 and its
natural or chemical ligands in HIV-1 infection and
in infection-related inflammation. The program
stems from the recognition of a critical mass of
basic and applied investigators already ongoing in
this Division and in the Department of Infectious
and Tropical Diseases on the role of CCR5 and its
ligands in HIV-1 infection and related clinical entities. The projects and their individual leaders have
already proven their validity and vitality in terms of
dedicated scientific publications, grants and
patents. However, they have never been coordinated as an internal network or program up to
date. Therefore, CHARM has the general goal to
create and foster such a network of knowledge
and mutual exchange of information, and collaborations by promoting their synergy, avoid duplicating efforts, and seeking for additional funding and
support both to individual projects and, hopefully,
to the Program as a whole.
2013 Achievements - In addition to several publications related to CHARM objectives by the program participants, we have mostly focused on the
use of Maraviroc (MVC), a CCR5 inhibitor, in the
treatment of primary HIV infection (PI: Dr.
Giuseppe Tambussi). In this regard, the potential
benefit of an early intervention could pave the way
for future therapies aimed at HIV eradication, such
as strategies to mobilize virus from latently infected CD4 cells or vaccine- and immune-based
therapies, which would have a greater probability
of success in patients whose reservoir has been
reduced by starting ART during PHI. An early
treatment could also potentially preserve the HIV-
specific immune response, thus increasing the
chances of a better control of viral replication.
Although the impact of viral production on the replenishment of HIV reservoir remains controversial, adopting an entry inhibitor molecule in the
course of chronic infection could potentially reduce the pool of latently infected cells to a lesser
extent if compared to standard ART regimens,
thus enhancing the infection prognosis and increasing future possibilities of viral eradication.
In a prospective trial (MAIN study, EUDRACT n°
2008-007004-29) conducted in our department
we enrolled PHI patients and assigned them to receive either MVC + standard cART or standard
cART alone for 48 weeks. At week 48, all the patients achieved plasma viremia levels <50 RNA
copies/ml. Both intention-to-treat and on-treatment analyses showed no differences between
groups in terms of mean CD4 T cell numbers and
plasma viremia at week 48. However, a better
performance in terms of CD4 T cell number gain
from baseline was observed in the MVC + cART
vs. cART alone groups. cART, whether or not associated with MVC, determined a significant decrease in the number of activated CD4 and CD8
T lymphocytes. Furthermore, we demonstrated a
significant increase in terminally differentiated CD8
T cells, usually reduced in chronic HIV infection.
Terminally differentiated CD4 T lymphocytes expressing CD127 (IL7-R ) were reduced in both
treatment groups, with patients who had received
MVC + ART showing a greater decrease (manuscript submitted). Overall, these findings suggest
that inhibition of CCR5 function by MVC may exert additional immunological benefit during cART
early immune reconstitution. The longer-term potential effects of these therapy regimens on virus
reservoirs are the object of ongoing follow-up
studies. The preliminary results of this study have
been presented at the following meetings:
• 20th Conference on Retroviruses and Opportunistic Infections, March 3-6 2013 Atlanta,
Georgia, USA (abs# H-124, M. Ripa winner of
young investigator award).
• Keystone Symposia: Immune Activation in HIV
Infection: Basic Mechanisms and Clinical Implications (D2) April 3, 2013 - April 8, 2013 Beaver Run Resort - Breckenridge, Colorado,
USA (abs# 3032).
• 5th Italian Conference on AIDS and retrovirusICAR 2013 - May 12-14 2013, Turin, Italy (abs#
CO13).
• 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Kuala Lumpur, Malaysia,
30 June-3 July 2013 (abs# WEPE449).
255
RESEARCH PROGRAMMES
Microenvironment and Genes in Cancers of the Blood
(MAGIC)
Co-Heads of Research Program:
Paolo Ghia* and Giovanni Tonon
Participating investigators:
Massimo Alessio, Center for Translational Genomics and BioInformatics
Angela Bachi, Division of Genetics and Cell biology
Matteo Bellone, Division of Immunology, Transplantation, and Infectious Diseases
Rosa Bernardi, Division of Molecular oncology
Stefano Biffo, Division of Molecular oncology
Attilio Bondanza, Division of Regenerative medicine, Stem cells, and Gene therapy
Chiara Bonini, Division of Regenerative medicine, Stem cells, and Gene therapy
Andrea Brendolan, Division of Molecular oncology
Valeria R. Caiolfa, Experimental Imaging Center
Federico Caligaris-Cappio, Division of Molecular oncology
Giulia Casorati, Division of Immunology, Transplantation, and Infectious Diseases
Simone Cenci, Division of Genetics and Cell biology
Fabio Ciceri, Division of Molecular oncology; Division of Regenerative medicine, Stem cells, and Gene
therapy
Angelo Corti, Division of Molecular oncology
Paolo Dellabona, Division of Immunology, Transplantation, and Infectious Diseases
Claudio Doglioni, Division of Molecular oncology
Marina Ferrarini, Division of Molecular oncology
Andrés José Marìa Ferreri, Division of Molecular oncology
Elisabetta Ferrero, Division of Molecular oncology
Katharina Fleischhauer, Division of Regenerative medicine, Stem cells, and Gene therapy
Paolo Ghia, Division of Molecular oncology
Luca G. Guidotti, Division of Immunology, Transplantation, and Infectious Diseases
Matteo Iannacone, Division of Immunology, Transplantation, and Infectious Diseases
RESEARCH PROGRAMMES
Cristina Maccalli, Division of Molecular oncology
Eugenio Montini, HSR-TIGET - The San Raffaele Telethon Institute for Gene Therapy
Marta Muzio, Division of Molecular oncology
Ruggero Pardi, Division of Immunology, Transplantation, and Infectious Diseases
Giorgio Parmiani, Division of Molecular oncology
Maurilio Ponzoni, Division of Molecular oncology
Maria Pia Protti, Division of Immunology, Transplantation, and Infectious Diseases
Vincenzo Russo, Division of Molecular oncology
Roberto Sitia, Division of Genetics and Cell biology
Giovanni Tonon, Division of Molecular oncology
Vision - Cancer development is due to a complex
interplay between genetic abnormalities arising
within the neoplastic clone and favourable stimuli
originating in the surrounding microenvironment.
Progress toward the cure of cancer can only
come from a deep understanding of all these factors and of the mechanisms through which they
concur toward tumor pathogenesis.
In this program, we focus on blood cancer involving B lymphocytes at different stages of differentiation namely acute lymphoblastic leukemia (ALL),
chronic lymphocytic leukemia (CLL), NonHodgkin Lymphomas (NHL) and multiple myeloma (MM). Despite major therapeutic advances, all
these tumors are presently incurable. Interestingly,
in all these malignancies, the interaction between
genetically abnormal malignant cells and a dysregulated microenvironment is playing a crucial
role in their pathogenesis. In details, all these malignancies carry a number of genetic abnormalities in multiple genes that control cell division, differentiation, survival or programmed cell death,
leading to unrestrained proliferation and accumulation. In addition, in each case the tumor microenvironment provides critical stimuli conferring
to malignant cells a growth advantage and an extended survival.
The rationale of this program relies on the idea
that effective and ultimately curative therapies for
these diseases could only emerge from targeting
simultaneously the tumour cell and its microenvironment interactions.
Goals - The aim of the Program is the identification of novel therapeutic targets at the forefront
between tumor cells and the microenvironment
that will allow defining new personalized treatment
strategies based on molecularly-based prognostic and predictive cards. We have devised 4 different interconnected Programs. Programs 1
(Novel Therapies) and 2 (Optimizing existing therapies and improving quality of life) deal with preclinical proof-of-principle studies of targeted approaches and the definition of novel prognostic
and predictive factors. Programs 3 (Novel targets)
and 4 (New cellular protagonists) are exploratory
in nature and aim at dissecting the role of novel
microenvironment molecular and cellular components whose significance has been strongly implied by preliminary data.
2013 achievements - During 2013, we have
achieved three main conclusions:
Conclusion 1. Chronic hematological neoplams
are characterized by active and dynamic microenvironments co-evolving with the leukemic clone
thereby supporting the evolution of more aggressive subclones and ultimately promoting disease
progression. The key role of active microenvironments acquires a clinical relevance especially in
the present era of non-genotoxic drugs.
Conclusion 2. The stratification of cancer patients
based upon gene/microenvironment interactions
may lead to more adequate treatment strategies
for specific categories of patients.
Conclusion 3. Our overall strategy aiming at unravelling the interaction between cancer cells and
their environment has led to the identification of
new promising therapeutic targets as well as the
potential therapeutic significance of some accessory cell populations that warrant further exploitation and pre-clinically validation.
During 2013, investigators participating in the program have produced data toward the development of a number of options that are ready to be
proposed to the scientific community. These include drugs targeting by-stander cells in CLL and
MM (conclusion 1), novel stratification strategies
for CLL patients incorporating stereotypy of the
Immunoglobulin receptors (conclusion 2), small
molecular drugs targeting intracellular pathways in
CLL and MM (conclusion 3) and chimeric antigen
receptors (CARs) redirecting T-cell specificity
against CLL and MM cells (conclusion 3). All
these have the potential to be moved rapidly toward clinical translation as new treatment and
prognostic approaches.
257
FACILITIES
CFCM, San Raffaele Core Facility for Conditional Mutagenesis ––––––––––––––––––– 260
SCIENTIFIC SUPERVISOR: Marco E. Bianchi*
FACILITY MANAGER: Lorenza Ronfani
FELLOWS: Lorenzo Benini, Ivana Benzoni
TECHNICIANS: Maria Luisa Pintonello, Rosanna Rinaldi
FRACTAL, Flow cytometry Resource, Advanced Cytometry –––––––––––––––––––––––– 261
Technical Applications Laboratory
SCIENTIFIC SUPERVISOR: Alessio Palini
FACILITY MANAGER: Chiara Villa
BIOLOGISTS: Simona Di Terlizzi, Federico Sizzano
TECHNICIANS: Emanuele Canonico, Ivan Muradore (until July 2013)
CERMAC, Centre of Excellence of High Field Magnetic Resonance –––––––––––––– 262
SCIENTIFIC SUPERVISOR: Enrico Smeraldi*
HEAD OF FACILITY: Andrea Falini*
PHYSICIAN: Valeria Blasi
RESIDENT: Claudia Godi**
POST-DOCTORAL FELLOWS: Sofia Crespi**, Roberta Longaretti
PHD STUDENTS: Antonella Castellano**, Sara Cirillo**
FELLOW: Paola Scifo
TECHNICIAN: Antonella Iadanza
PROMIFA, PROtein MIcrosequencing FAcility ––––––––––––––––––––––––––––––––––––––––– 262
SCIENTIFIC SUPERVISOR: Marco E. Bianchi* (ad interim)
FACILITY MANAGER: Annapaola Andolfo
TECHNICIAN: Cinzia Magagnotti
Mouse histopathology –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 263
SCIENTIFIC SUPERVISOR: Claudio Doglioni*
FACILITY MANAGER: Francesca Sanvito
PHYSICIAN: Maurilio Ponzoni
TECHNICIANS: Anna Innocenzi, Martina Rocchi
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
259
FACILITIES
CFCM, San Raffaele-Telethon Core Facility for Conditional
Mutagenesis
Transgenic and knock-out mice are widely used in
the research because of their high impact in the
understanding of the proteins functional role and
because they constitute models to study genetic
diseases.
The San Raffaele Core Facility for Conditional Mutagenesis (CFCM) has been operative since 1999.
During this time CFCM has provided to the Scientific Community more than 400 murine models.
CFCM performs pronuclear injections and lentiviral infections to generate transgenic mice, offers
the electroporation of Embryonic Stem cell (ES
cells) and morulae and blastocysts injections of
recombinant clones to generate gene targeted
models. Moreover, CFCM carries out rederivations of mice via embryo transfer. In addition,
CFCM helps Researchers to plan experiments, to
manipulate and genotype mice.
Other services provided by CFCM are the screening of resistant clones by Southern Blotting.
Figure 44. Microinjection of ES cells into a morula
CFCM performs the De novo Isolation of ES cells
from wild type and mutant bastocysts. ES cells
derived from transgenic mice represent important
tools for the analysis of the mutation of interest.
Moreover, Researchers have the possibility to differentiate ES cells in all cell lineages.
Very important, CFCM performs Embryo Cryopreservation. This is a basic service because Researchers spent time and money to maintain
murine lines, which are not necessary for their
current studies. Moreover, these murine lines occupy precious space in the Animal House.
During 2013, CFCM generated 7 new gene-targeted murine models and 4 new transgenic lines.
11 and 30 murine lines were, respectively, cryopreserved and rederived.
More information can be found at the site
http://www.hsr.it/research/organization/servicesopen-labs/cfcm/.
Lorenza Ronfani
FACILITIES
FRACTAL, Flow cytometry Resource, Advanced Cytometry
Technical Applications Laboratory
The Flow cytometry Resource and Advanced Cytometry Technical Applications Laboratory (FRACTAL) is a core facility that offers state-of-the-art instrumentation and analysi stechniques to the scientific community. Flow cytometry is an evolving
field and scientists approach this technology to
answer a multitude of questions in their discovery
work. FRACTAL supports researchers in obtaining
verifiable results for such applications as Immunophenotyping, Cell division and Apoptosis,
Cell activation, Intracellular pH shifts, Phagocytosis, Oxidative burst and many more. So wide
ranging is the applicability of this technology thatpractitioners may include, in addition to biologists,
physicians, microbiologists, marinebiologists, veterinarians and research chemists to name a few.
In line with this inter-disciplinary environment,
FRACTAL is now implementing a “Translational
Cytometry” program aimed to develop its own
projects that bridge research and clinical protocols, for which cytometry analysis is essential. In
addition to the analytical capabilities of this technique, the core facility offers assisted cell Sorting
services for characterizing, separating and purifying populations of particles as diverse as beads,
bacteria, micro-particles, cells and chromosomes. In 2010 the facility achieved ISO
9001:2008 Certification for the processes of Cell
Sorting, Assisted Analysis and Training. Additionally, the facility supported over 400 Researchers,
performed more than 1361 cell sorts and logged
over 8,000 hours of analytical instrument time.
Chiara Villa
Figure 45. Interrogation point on Moflo XDP
261
FACILITIES
CERMAC, Centre of Excellence of High Field Magnetic
Resonance
The Centre of Excellence High Field MRI or CERMAC start operations in 2003 with testing of the 3
Tesla magnet that constitutes the instrumental
core of the Center. Around the high field magnet
develops a two-story structure housing offices
equipped with all the workstations and computers
necessary to post-process images and their
analysis. The building is located within the Unit of
Neuroradiology at the Hospital San Raffaele in Milan.
The creation of a Centre of Excellence based on
the use of a high-field MRI has become possible
thank to the initial presence at the Faculty of Medicine and Psychology, University Vita-Salute San
Raffaele and at the homonymous Scientific Institute of personnel with high expertise in neuroradiology, functional neuroimaging, neurology, cognitive neuroscience, psychiatry, neurosurgery and
oncology, and integration of these disciplines with
physical and engineering skills. The integration of
the different afferents having great scientific and
cultural significance have made vital and highly
productive in terms of research, teaching and
training a multidisciplinary center based on neuroimaging.
Scientists of different disciplines work together
carrying on projects concerning development and
validation of functional MR techniques and their
application in the field of neuroscience (neuroradiology, neurology, neurosurgery, psichiatry, psichology and cognitive neurosciences). Advanced
MR techniques are employed to investigate normal brain development and function with special
focus on myelination process, music comprehension, white matter connections, language areas
and mirror neuron system.The same techniques
are used to characterize morphological, structural
and functional modifications related to degenerative, inflammatory, neoplastic and vascular diseases. A novel approach to psychiatric diseases
has been enabled by the noninvasive MR capabilities. More than hundred papers have been published in major international journals during the last
five years. The Center is site for postgraduate and
PhD training in neuropsychology, cognitive neuroscience, neurology and psychiatry. Medicine, Psichology, Biotechnology and Physiotherapy students complete their thesis at CERMAC.
Andrea Falini
ProMiFa, Protein Microsequencing Facility
During the last year, the facility could further extend its portfolio by increasing the number of internal (up to 15) and external users (4 companies
and a total of 16 between academic and no profit
institutions). The activities of the facility can be described as below:
1. Protein characterization
• MW determination of peptides or proteins by
MALDI-MS or ESI-MS and sequencing by tandem mass spectrometry (MS/MS).
2. Protein identification
• Protein identification in gel bands or spots by
MALDI-MS or nanoLC followed by ESI- MS/MS.
• Post-translational modifications (PTMs)-characterization by MS/MS, including type and site.
• Phosphorylation characterization: phosphorylated peptides are enriched using affinity columns
(TiO2 or IMAC) and then analyzed by MS.
3. Biomarker profiling in biological samples by
2DE, image analysis and statistical evaluation
• Analysis of the entire proteome in complex samples by 2D-electrophoresis, followed by acqui-
sition of high definition images to evaluate the
differential protein expression pattern in tissues
and biological fluids.
4. Protein quantification in biological samples by
MS/MS analyses
• Protein quantification in complex samples by label-free or labelling approaches, including
metabolic labelling of living cells using Stable
isotope labelling by amino acids in cell culture
(SILAC) and dimethyl-labelling of digested proteins.
5. Instrumentation
• LTQ Orbitrap XL mass spectrometer equipped
with an Easy nLC
• Voyager DE-STR MALDI-TOF mass spectrometer
Moreover, in order to develop a metabolomics/
lipidomics platform, the acquisition of two new instrumentations was indicated.
More information can be found at the site:
www.promifa-protein-microsequencing-facility/
Annapaola Andolfo
FACILITIES
Figure 46. Typical workflow for the analysis of the entire proteome in complex samples by 2D-electrophoresis,
followed by acquisition of high definition images to evaluate the differential protein expression pattern in biological
fluids. Mass spectrometry identification of proteins and their validation by an independent technique help to
specifically define the treatment strategy for patients. Reprinted from: Calcium signaling-related proteins are
associated with broncho-pulmonary dysplasia progression. Magagnotti, C and Matassa, PG; Bachi, A;
Vendettuoli, V; Fermo, I; Colnaghi, MR; Carletti, RM; Mercadante, D; Fattore, E; Mosca, F; Andolfo, A. J.
Proteomics: 2013; 94: 401-412 doi: 10.1016/j.jprot.2013.10.007 © 2013, with permission from Elsevier.
Mouse histopathology
The principal aim of the Mouse Histopathology
Unit is to support, complement and favour the advancement of scientific projects, by providing
conventional morphological analysis and immunophenotyping, in order to evaluate the presence of morphological alterations in mouse models of human disease.
The facility is located in the Department of Pathology and offers the technical and the interpretative
experience for the analysis of tissues from animal
models, evaluating the best histological or immunocytochemical procedures, based on the expected results.
The services provided include:
• frozen tissues and cryostatic section preparation
• immunohistochemistry (commercial antibody
and new ones to be set up)
• cytospin and paraffin cytoblock
• final report
1. macroscopic examination including perfusion
and necropsy
To date multiple collaborations within our Institute
and with research groups from other Institutes have
been settled in order to analyze the morphological
and immunophenotypical patterns of murine models of diseases, treated with different therapeutic
approaches and to analyze the efficacy of gene
therapy and safety of the use of viral vectors.
Francesca Sanvito
2. microscopic analysis
• paraffin embedding and inclusion
• microtome sectioning and standard HE staining
• special histochemical staining (Perls, PAS, Masson, Gomori stainings, etc.)
3. image analysis
The role of pathology in the field of experimental
studies on laboratory animal is of interest for:
• indentification and evaluation of experimentally
induced lesions
• setting of animal models of human diseases
• efficacy and safety studies
• phenotyping of transgenic mice
263
FACILITIES
FRACTAL, Flow cytometry Resource, Advanced Cytometry Technical Applications Laboratory
CFCM, San Raffaele-Telethon Core Facility for Conditional Mutagenesis
FACILITIES
PROMIFA, PROtein MIcrosequencing FAcility
265
THE
ETHICS
COMMITTEE
The Ethics Committee of the Scientific Institute Hospital San Raffaele - Milano
Established Pursuant to M.D. 08022013
Until October 2013
CHAIRMAN: Gianna Zoppei, San Raffaele Scientific Institute
VICE CHAIRMAN: Guido Pozza, Physician, Professor Emeritus of Internal Medicine, Università VitaSalute San Raffaele
SECRETARY: Alfredo Anzani, Expert in Bioethics, San Raffaele Scientific Institute
MEMBERS:
Giliola Calori, Biostatistician, San Raffaele Scientific Institute
Ilaria Carretta, Psychologist and Psychoterapist, San Raffaele Scientific Institute
Francesco Caviezel, Physician, Professor Emeritus of Endocrinology, University of Milan
Maurizio Chiodi, Theologian, Professor at the Theological Faculty of Northern Italy, Milan
Francesco Clementi, Pharmacologist, Professor Emeritus of Pharmacology, University of Milan
Maria Grazia Fusi, Regional Area GPs, Milan
Andrea Gentilomo, Medical Examiner, Professor of Legal Medicine, University of Milan
Roberts Mazzuconi, Hospital Director, San Raffaele Scientific Institute, ex officio
Massimo Reichlin, Expert in Bioethics, Professor of Phylosophy, Università Vita-Salute San Raffaele
Maria Grazia Roncarolo, Scientific Director, San Raffaele Scientific Institute, ex officio
Claudio Rugarli, Physician, Professor Emeritus of Internal Medicine, Università Vita-Salute San Raffaele
Patrizia Tadini, Pharmacist, San Raffaele Scientific Institute, ex officio
Cesare Triberti, Expert in Legal Procedures
Liliana Villa, Representative of the Fondazione Centro San Raffaele del Monte Tabor
Ewa Wysocka, Representative of Nursing Area
Maria Elisabetta Zanardelli, Volunteer association member, Associazione per l’Aiuto ai Giovani Diabetici
(Onlus)
CONSULTANTS:
Cesarina Curti, Expert in Medical Devices, San Raffaele Scientific Institute
Gianvincenzo Zuccotti, Head of Pediatrics Unit, Luigi Sacco Hospital, Milan
Since November 2013
MEMBERS:
Anzani Alfredo, Physician, San Raffaele Hospital, President of the Ethic’s Committee
Pozza Guido, Physician, San Raffaele Hospital, Vice-President of the Ethic’s Committee
Arrigoni Cristina, Representative of healthcare professions area, University of Pavia
Basile Giuseppe, Legal Doctor, Galeazzi Orthopaedic Institute
Cabitza Paolo, Expert in Medical Devices, San Donato Polyclinic
Calori Giliola, Biostatistician, San Raffaele Hospital
Carretta Ilaria, Expert in Psychology, San Raffaele Hospital
Chiodi Maurizio, Expert in Moral Theology, Faculty of Theology, Milan University
Chiumello Giuseppe, Head Physician in Paediatrics, San Raffaele Hospital – University Vita-Salute
San Raffaele
Clementi Francesco, Pharmacologist, Professor Emeritus of Pharmacology, University of Milan
Colloca Stefano, Bioethicist, University of Pavia
Ferrari Maurizio, Geneticist, San Raffaele Hospital – University Vita-Salute San Raffaele
Martinelli Vittorio, Physician, San Raffaele Hospital
Meola Giovanni, Physician, San Donato Polyclinic – University of Milan
Micieli Giuseppe, Physician, Mondino Neurological Institute
Orlando M. Elisabetta, Member of Volunteer association
Procopio Giuseppe, Physician, National Cancer Institute, Milan
Reichlin Massimo, Bioethicist, University Vita-Salute San Raffaele
Richelmi Plinio, Pharmacologist, University of Pavia
Sorghi Massimo, General Practitioner, Milan 2 Area
Tadini Patrizia, Pharmacist, San Raffaele Hospital
Zoppei Gianna, Expert in Humanization of Care, San Raffaele Hospital
MEMBERS IN RELATION TO QUALIFICATION
Luciani Diego, Clinical Engineer, San Raffaele Hospital
Pontiroli Antonio, Expert in Diabetes and Nutrition, University of Milan
Triberti Cesare, Expert in Health Law
MEMBERS OF THE SCIENTIFIC INSTITUTE HOSPITAL SAN RAFFAELE
Mazzuconi Roberts, Health Care Director, San Raffaele Hospital
Mandelli Paolo, Substitute of the Health Care Director, San Raffaele Hospital
Tadini Patrizia, Pharmacist, San Raffaele Hospital
Franzin Michela, Substitute of the Pharmacist, San Raffaele Hospital
Montorsi Francesco, Scientific Director, San Raffaele Hospital
Guidotti Luca, Substitute of the Scientific Director, San Raffaele Hospital
MEMBERS OF THE SCIENTIFIC INSTITUTE SAN DONATO
Cuppone M. Teresa, Health Care Director, San Donato Polyclinic
Carpinelli Luca, Substitute of the Health Care Director, San Donato Polyclinic
Cavallazzi Mario, Pharmacist, San Donato Polyclinic
Felisatti Monica, Substitute of the Pharmacist, San Donato Polyclinic
Tettamanti Guido, Scientific Director, San Donato Polyclinic
Menicanti Lorenzo, Substitute of the Scientific Director, San Donato Polyclinic
MEMBERS OF THE ORTHOPAEDIC SCIENTIFIC INSTITUTE GALEAZZI
Pregliasco Fabrizio, Health Care Director, Galeazzi Orthopaedic Institute
Vinci Anna, Substitute of the Health Care Director, Galeazzi Orthopaedic Institute
267
THE ETHICS COMMITTEE
Cavallazzi Mario, Pharmacist, Galeazzi Orthopaedic Institute
Felisatti Monica, Substitute of the Pharmacist, Galeazzi Orthopaedic Institute
Banfi Giuseppe, Scientific Director, Galeazzi Orthopaedic Institute
Cittera Elena, Substitute of the Scientific Director, Galeazzi Orthopaedic Institute
MEMBERS OF THE NEUROLOGICAL SCIENTIFIC INSTITUTE MONDINO
Moneta Angela, Health Care Director, Mondino Institute
Gervasio Luisa, Pharmacist, Mondino Institute
Nappi Giuseppe, Scientific Director, Mondino Institute
Blandini Fabio, Substitute of the Scientific Director, Mondino Institute
MEMBERS OF SAN RAFFAELE TURRO INSTITUTE
Mazzitelli Salvatore, Health Care Director, San Raffaele Turro Institute
Benedetti Francesco, Substitute of the Health Care Director, San Raffaele Turro Institute
Tadini Patrizia, Pharmacist, San Raffaele Turro Institute
Franzin Michela, Substitute of the Pharmacist, San Raffaele Turro Institute
MEMBERS OF SANT’AMBROGIO E SAN SIRO INSTITUTES
Bissolati Morena, Health Care Director, Sant’Ambrogio e San Siro Institutes
Cirri Silvia, Substitute of the Health Care Director, Sant’Ambrogio e San Siro Institutes
Felisatti Monica, Pharmacist, Sant’Ambrogio e San Siro Institutes
Cavallazzi Mario, Substitute of the Pharmacist, Sant’Ambrogio e San Siro Institutes
THE CLINICAL DEPARTMENTS
269
CARDIO-THORACIC-VASCULAR
DEPARTMENT
Head of Department:
Ottavio Alfieri*
DEPARTMENT AREA COORDINATORS: Stefano Benussi, Renata Clotilde Castellano, Domenico
Cianflone*, Guglielmo Cornero, Stefano Gerosa, Giovanni La Canna, Silvio Magrin, Enrico Maria
Marone, Germano Melissano*, Stefano Moriggia
Cardiac surgery
HEAD OF UNIT: Ottavio Alfieri*
CLINICAL UNIT LEADERS: Stefano Benussi, Andrea Blasio, Michele De Bonis, Francesco Maisano,
Stefano Moriggia, Alessandra Rossodivita
CLINICAL UNIT COORDINATOR: Alessandro Castiglioni
PHYSICIANS: Andrea Blasio, Maria Chiara Calabrese, Micaela Cioni, Paolo Denti, David Ferrara,
Andrea Fumero, Giuseppe Iaci, Elisabetta Lapenna, Simona Nascimbene, Maria Grazia Pala,
Alessandro Verzini
RESIDENTS: Nicola Buzzati, Marta Casamassima, Andrea Giacomini, Mikel Kamami, Teodora Nisi,
Elena Portinaro, Alberto Pozzoli, Maurizio Taramasso, Cinzia Trumello
FELLOWS: Andrea Guidotti, Davide Schiavi
Echocardiography Unit
HEAD OF UNIT: Giovanni La Canna
PHYSICIANS: Emanuela Alati, Giovanna Di Giannuario
FELLOW: Chiara Sordelli
TECHNICIAN: Marta Martino
Cardiovascular rehabilitation and prevention
HEAD OF UNIT: Domenico Cianflone*
CLINICAL UNIT LEADER: Carlo Meloni
PHYSICIANS: Maria Avitabile, Nicole Cristell, Marco Magnoni
RESIDENTS: Francesco Ancona, Letizia Fausta Bertoldi, Alessandro Durante, Alessandra Laricchia,
Giovanni Peretto, Marco Spartera
FELLOW: Luca Rosario Limite
Cardiovascular interventions Unit
HEAD OF UNIT: Antonio Colombo
CLINICAL UNIT LEADERS: Mauro Carlino, Alaide Chieffo, Matteo Montorfano
PHYSICIANS: Alfredo Castelli, Filippo Figini, Azeem Mohamed Latib
FELLOWS: Chiara Bernelli, Jaclyn Chi Lin Chan, Georgina Fuertes, Caroline J. Magri, Charbel A. Naim,
Vasilis Panoulas, Paola Spatuzza
TRIAL COORDINATOR: Angela Ferrari
271
THE CLINICAL DEPARTMENTS
TECHNICIANS: Gianfranco Accarino, Raimondo Bellanca, Salvatore Cannavale, Andrea Di Marco,
Fanny Lavazza, Matteo Longoni, Davide Maccagni, Massimo Angelo Messa, Marcello Murino,
Vittorio Romano, Mario Squilla
Clinic for primary and secondary cardiomyopathy
HEAD OF UNIT: Paolo Camici*
PHYSICIANS: Sara Benedetti, Roberto Spoladore**
RESIDENTS: Alessandro Durante**, Alessia Faccini**, Francesco Maranta**, Damiano Regazzoli**
FELLOWS: Alberto Castella, Umberto Gianni
Arrhythmia Unit and electrophysiology laboratories
HEAD OF UNIT: Paolo Della Bella
CLINICAL UNIT LEADERS: Giuseppe Maccabelli, Patrizio Mazzone
PHYSICIANS: Caterina Bisceglia, Manuela Cireddu, Simone Gulletta, Gabriele Paglino, Simone Sala,
Nicola Trevisi
CONSULTANTS: Francesca Baratto, Alessandra Marzi, Andrea Radinovic, Nicoleta Sora, Pasquale
Vergara
POST-DOCTORAL FELLOWS: Amr Nawar, Miki Yamase, Luck Yonguanijchit
Clinical cardiology and outpatient clinic
HEAD OF UNIT: Alberto Margonato*
CLINICAL UNIT LEADERS: Fabrizio Bonetti, Alberto Cappelletti, Andrea Conversano, Gabriele
Fragasso, Stefano Gerosa, Cosmo Godino, Michele Oppizzi
PHYSICIANS: Eustachio Agricola, Chiara Camesasca, Cristina Canciani, Barbara Demarchi, Valeria
Magni, Alessandra Mailhac, Cinzia Nitti, Alessandra Pancaldi, Marco Papa, Cristina Pedrigi, Patrizia
Puccetti, Carmen Silipigni
RESIDENTS: Monica Mazzavillani, Claudia Montanaro, Anna Salerno **
Coronary Care Unit (CCU)
HEAD OF UNIT: Alberto Margonato*
CLINICAL UNIT LEADERS: Carlo Ballarotto, Giuseppe Pizzetti
PHYSICIANS: Michela Cera, Massimo Slavich, Roberto Spoladore
Functional rehabilitation
HEAD OF UNIT: Alessandra Raschi
Intensive Care Unit (ICU) and Post Operatory Care Unit (POCU)
HEAD OF UNIT: Alberto Zangrillo*
CLINICAL UNIT COORDINATORS: Tiziana Bove, Maria Grazia Calabrò, Giovanni Landoni*, Federico
Pappalardo, Anna Mara Scandroglio
PHYSICIANS: Elena Bignami, Francesco Cama, Andrea Carozzo, Francesca Cavenago, Guglielmo
Cornero, Remo Daniel Covello, Antonella Crescenti, Martina Crivellari, Monica De Luca, Greta
Fano, Rossana Fiori, Annalisa Franco, Giovanna Frau, Chiara Gerli, Silvio Magrin, Giovanni Marino,
Giulio Melisurgo, Roberta Mennella, Melissa Messina, Fabrizio Monaco, Jaques N’Zepa Batonga,
Nicola Pasculli, Ornella Sottocorna
Thoracic surgery
HEAD OF UNIT: Piero Zannini*
CLINICAL UNIT LEADERS: Giulio Melloni, Giampiero Negri*,
CLINICAL UNIT COORDINATOR: Angelo Carretta
PHYSICIANS: Alessandro Bandiera, Paola Ciriaco, Armando Puglisi
RESIDENTS: Piergiorgio Muriana, Silvia Raimondi Cominesi, Stefano Viscardi
THE CLINICAL DEPARTMENTS
Vascular surgery
HEAD OF UNIT: Roberto Chiesa*
CLINICAL UNIT LEADERS: Efrem Civilini, Enrico Maria Marone, Germano Melissano*, Yamume
Tshomba
CLINICAL UNIT COORDINATOR: Renata Clotilde Castellano
PHYSICIANS: Domenico Astore, Laura Dordoni, Gloria Esposito, Massimiliano Marrocco-Trischitta
RESIDENTS: Luca Apruzzi**, Serena Frezza**, Jessica Lanza, Davide Logaldo, Daniele Mascia**,
Girolomina Mazzeo, Enrico Rinaldi**, Sara Spelta, Renato Vitale**
FELLOWS: Domenico Baccellieri, Luca Bertoglio, Chiara Brioschi, Andrea Kahlberg
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
The clinical activity of the Department is devoted to the diagnosis and treatment of cardiac, thoracic
and vascular disease.
New techniques and technologies have been introduced to offer to the patients the entire spectrum of
the therapy options in a multidiciplinary environment.
Patients-centered care is the philosophy behind the daily clinical practice.
The interaction among different specialists (anesthesiologists, cardiovascular and thoracic surgeons, interventional and clinical cardiologists) is favored by the contiguity of the areas devoted to surgery, cath
lab procedures and intensive care.
Patients with acute disease coming on emergency basis as well as patients with chronic diseases admitted electively are submitted to diagnostic investigation, treatment and then rehabilitation if needed. A
well structured rehabilitation program is available providing complete recovery even for the sickest patients.
An active outpatient clinic is functioning for new referrals and follow-up.
Clinical activity and areas of excellence
In regard to cardiac diseases, the main pathologies are ischemic and valvular heart diseases, which are
treated either with catheter based interventions or minimally invasive procedures or conventional surgery.
Grown-up patients with congenital heart disease have been increased recently. A large number of patients
with major aortic and vascular pathologies are also increasingly referred as well as patients with complex
oncological problems of the thoracic organs.
Transcatheter aortic valve implantation has been widely carried out to treat inoperable or high risk patients with severe aortic stenosis and today the largest experience in Italy has been accumulated in this
field by our multidisciplinary team.
The percutaneous treatment of mitral insufficiency is performed in patients with heart failure and our series represents one of the very first in Europe.
Innovative modalities of medical treatment for patients with congestive heart failure have been recently introduced, particularly in the field of improvement of cardiac metabolism, achieving a significant increaseof
survival/quality of life as compared to figures reported in the literature.
A structurized program for the treatment of patients with end-stage heart failure has been developed.
Aim of the program is to provide a comprehensive treatment for the failing heart, including mechanical circulatory support (short and long term) in different clinical settings: post cardiotomy cardiogenic shock,
acute myocardial infarction, bridge to transplant, destination therapy. Also treatment of acute hypoxia and
ARDS by ECMO is now offered as a life-saving procedure.
A wide spectrum of aortic pathologies, including aneurysms, dissection, traumatic injuries, coarctation,
etc., are treated using both conventional and endovascular approaches. For high risk patients with complex aortic arch and thoracoabdominal pathology, hybrid open and endovascular branch-technology is
currently under evaluation. Both open and endovascular procedures are also used for carotid and lower
limb revascularization.
Great experience has been achieved in the treatment of patients with ventricular tachycardia, who are re273
THE CLINICAL DEPARTMENTS
ferred from all over the country. Other major arrhythmias are treated by electrophysiologists and surgeons
in the cath lab and in the operating room.
A great recent achievement in thoracic surgery has been the treatment of lung cancer in patients with emphysema. The respiratory impairment due to this disease used to be a surgical contraindication in the past.
Today different strategies have been introduced in our Department to extend surgical indication in lung
cancer including parenchyma-sparing bronchoplasty techniques, lung volume reduction surgery and
bronchoscopic lung volume reduction.
Finally, 3-D echocardiography has been introduced as a routine imaging modality to assess patients with
structural heart disease, with considerable enhancement of diagnostic capabilities.
Ottavio Alfieri
Selected publications
Ammirati, E; Cristell, N; Cianflone, D; Vermi, AC; Marenzi, G; De Metrio, M; Uren, NG; Hu, D; Ravasi, T; Maseri, A; Cannistraci, CV. Questing for circadian dependence in ST-segment-elevation
acute myocardial infarction: a multicentric and multiethnic study. Circ. Res.: 2013; 112(10): e110e114 - Article
Buzzatti, N; Maisano, F; Latib, A; Cioni, M; Taramasso, M; Mussardo, M; Colombo, A; Alfieri,
O. Computed tomography-based evaluation of aortic annulus, prosthesis size and impact on early
residual aortic regurgitation after transcatheter aortic valve implantation. Eur. J. Cardiothorac. Surg.:
2013; 43(1): 43-51 - Article
Chieffo, A and Buchanan, GL; Van Mieghem, NM; Tchetche, D; Dumonteil, N; Latib, A; Van Der
Boon, RMA; Vahdat, O; Marcheix, B; Farah, B; Serruys, PW; Fajadet, J; Carrie, D; De Jaegere, PPT;
Colombo, A. Transcatheter aortic valve implantation with the Edwards SAPIEN versus the medtronic corevalve revalving system devices: A multicenter collaborative study: The PRAGMATIC plus initiative (Pooled-RotterdAm-Milano-Toulouse in Collaboration). J. Am. Coll. Cardiol.: 2013; 61(8): 830836 - Article
Chiesa, R; Tshomba, Y; Mascia, D; Rinaldi, E; Logaldo, D; Civilini, E. Open repair for juxtarenal
aortic aneurysms. J. Cardiovasc. Surg.: 2013; 54(1 SUPPL.1): 35-45 - Review
Citro, R; Mirra, M; Baldi, C; Prota, C; Palumbo, B; Piscione, F; La Canna, G. Concomitant dynamic
obstruction and endocarditis after “valve in valve” TAVI implantation. Int. J. Cardiol.: 2013; 167(2):
e27-e29 - Letter
De Bonis, M; Lapenna, E; Buzzatti, N; Taramasso, M; Calabrese, MC; Nisi, T; Pappalardo, F;
Alfieri, O. Can the edge-to-edge technique provide durable results when used to rescue patients
with suboptimal conventional mitral repair?. Eur. J. Cardio-thorac. Surg.: 2013; 43(6): e173-e179 Article
Della Bella, P; Baratto, F; Tsiachris, D; Trevisi, N; Vergara, P; Bisceglia, C; Petracca, F; Carbucicchio, C; Benussi, S; Maisano, F; Alfieri, O; Pappalardo, F; Zangrillo, A; Maccabelli, G. Management of ventricular tachycardia in the setting of a dedicated unit for the treatment of complex
ventricular arrhythmias: Long-term outcome after ablation. Circulation: 2013; 127(13): 1359-1368 Article
Farooq, V and Van Klaveren, D; Steyerberg, EW; Meliga, E; Vergouwe, Y; Chieffo, A; Kappetein,
AP; Colombo, A; Holmes ,Jr DR; MacK, M; Feldman, T; Morice, MC; Stahle, E; Onuma, Y; Morel,
MA; Garcia-Garcia, HM; Van Es, GA; Dawkins, KD; Mohr, FW; Serruys, PW. Anatomical and clinical
characteristics to guide decision making between coronary artery bypass surgery and percutaneous
coronary intervention for individual patients: Development and validation of SYNTAX score II. Lancet:
2013; 381(9867): 639-650 - Article
Fragasso, G; Rosano, G; Baek, SH; Sisakian, H; Di Napoli, P; Alberti, L; Calori, G; Kang, SM; Sahakyan, L; Sanosyan, A; Vitale, C; Marazzi, G; Margonato, A; Belardinelli, R. Effect of partial fatty
acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: Results from an
international multicentre retrospective cohort study. Int. J. Cardiol.: 2013; 163(3): 320-325 - Article
THE CLINICAL DEPARTMENTS
Godino, C; Lauretta, L; Pavon, AG; Mangieri, A; Viani, G; Chieffo, A; Galaverna, S; Latib, A;
Montorfano, M; Cappelletti, A; Maisano, F; Alfieri, O; Margonato, A; Colombo, A. Heyde’s syndrome incidence and outcome in patients undergoing transcatheter aortic valve implantation. J. Am.
Coll. Cardiol.: 2013; 61(6): 687-689 - Letter
Gould, KL; Johnson, NP; Bateman, TM; Beanlands, RS; Bengel, FM; Bober, R; Camici, PG; Cerqueira, MD; Chow, BJ; Di Carli, MF; Dorbala, S; Gewirtz, H; Gropler, RJ; Kaufmann, PA; Knaapen,
P; Knuuti, J; Merhige, ME; Rentrop, KP; Ruddy, TD; Schelbert, HR; Schindler, TH; Schwaiger, M;
Sdringola, S; Vitarello, J; Williams Sr, KA; Gordon, D; Dilsizian, V; Narula, J. Anatomic versus physiologic assessment of coronary artery disease. Role of coronary flow reserve, fractional flow reserve,
and positron emission tomography imaging in revascularization decision-making. J. Am. Coll. Cardiol.: 2013; 62(18): 1639-1653 - Review
Lancellotti, P; Rosenhek, R; Pibarot, P; Iung, B; Otto, CM; Tornos, P; Donal, E; Prendergast, B; Magne, J; La Canna, G; Pierard, LA; Maurer, G. ESC Working Group on Valvular Heart Disease Position Paper-heart valve clinics: Organization, structure, and experiences. Eur. Heart J.: 2013; 34(21):
1597-1606 - Article
Magnoni, M; Figini, F; Piraino, D; Cianflone, D. Coexistence of multiple and widespread cardiovascular complications in a patient with Marfan syndrome. J. Clin. Ultrasound: 2013; 41(3): 195-198
- Article
Mancini, M; Petretto, E; Kleinert, C; Scavone, A; De, T; Cook, S; Silhavy, J; Zidek, V; Pravenec, M;
d’Amati, G; Camici, PG. Mapping genetic determinants of coronary microvascular remodeling in the
spontaneously hypertensive rat. Basic Res. Cardiol.: 2013; 108(1): article 316 - Article
Melloni, G; Samanes Gajate, AM; Sestini, S; Gallivanone, F; Bandiera, A; Landoni, C; Muriana,
P; Gianolli, L; Zannini, P. New positron emission tomography derived parameters as predictive factors for recurrence in resected stage i non-small cell lung cancer. Eur. J. Surg. Oncol.: 2013; 39(11):
1254-1261 - Article
Mizuno, H; Vergara, P; Maccabelli, G; Trevisi, N; Colombo; S; Brombin, C; Mazzone, P; Della
Bella, P. Contact force monitoring for cardiac mapping in patients with ventricular tachycardia. J.
Cardiovasc. Electrophysiol.: 2013; 24(5): 519-524 - Article
Negri, G; Bandiera, A; Carretta, A; Puglisi, A; Mandelli, C; Ciriaco, P; Zannini, P. Unusual presentation of mediastinal neurogenic tumours. Case Rep. Surg.: 2013; 2013: 414260 - Case report
Pappalardo, F; Pieri, M; Greco, T; Patroniti, N; Pesenti, A; Arcadipane, A; Ranieri, VM; Gattinoni,
L; Landoni, G; Holzgraefe, B; Beutel, G; Zangrillo, A; on behalf of the Italian ECMOnet. Predicting
mortality risk in patients undergoing venovenous ECMO for ARDS due to influenza A (H1N1) pneumonia: the ECMOnet score. Intensive Care Med.: 2013; 39(2): 275-281 - Article
Pasin, L; Landoni, G; Zangrillo, A. Glutamine and antioxidants in critically ill patients. New Engl. J.
Med.: 2013; 369(5): 482-484 - Letter
Scheinert, D; Pratesi, C; Chiesa, R; Coppi, G; Brunkwall, JS; Klarenbeek, G; Cebrian, A; Torsello,
G. First-in-human study of the INCRAFT endograft in patients with infrarenal abdominal aortic
aneurysms in the INNOVATION trial. J. Vasc. Surg.: 2013; 57(4): 906-914 - Article
275
DEPARTMENT
OF
GENERAL AND
SPECIALISTIC SURGERY
Department coordinator:
Gianfranco Ferla*, since November 2013
Head of Department:
Carlo Staudacher* until October 2013
DEPARTMENT AREA COORDINATORS: Marco Braga*, Francesco Deni, Renato Finazzi, Emiliano
Giorgi, Gilberto Mari, Michele Paganelli, Danilo Parolini, Sandro Passaretti, Carlo Socci
Gastroenterologic surgery
HEAD OF UNIT: Gianfranco Ferla* (ad interim) since November 2013; Carlo Staudacher*, until
October 2013
CLINICAL UNIT LEADERS: Saverio Di Palo, Elena Orsenigo, Danilo Parolini, Carlo Socci
CLINICAL UNIT COORDINATOR: Paola De Nardi
PHYSICIANS: Andrea Marco Tamburini, Andrea Vignali
RESIDENTS: Massimiliano Bissolati**, Damiano Chiari**, Guido Fiorentini**, Paolo Giovanni Gazzetta**,
Luca Ghirardelli**, Francesca Muffatti**
General and pancreatic surgery
HEAD OF UNIT: Gianfranco Ferla* (ad interim) since November 2013; Carlo Staudacher*, until
October 2013
CLINICAL UNIT LEADERS: Gianpaolo Balzano, Marco Braga*
RESEARCHER: Lorenzo Piemonti
PHYSICIAN: Renato Castoldi
RESIDENTS: Riccardo Ariotti**, Giovanni Luigi Capretti**, Cristina Gilardini**
Hepatobiliary and week surgery
HEAD OF UNIT: Gianfranco Ferla*
CLINICAL UNIT LEADERS: Luca Aldrighetti, Edoardo Beretta, Alberto Marassi, Gilberto Mari
PHYSICIANS: Marco Catena, Enrico Fiacco, Renato Finazzi, Michele Paganelli
CONSULTANTS: Mvunde Mukenge, Veronica Zuber
RESIDENTS: Federica Cipriani**, Annalisa Gagliano**, Francesca Ratti**
FELLOW: Fabio Ferla
THE CLINICAL DEPARTMENTS
Orthopaedics
HEAD OF UNIT: Gianfranco Fraschini*
CLINICAL UNIT LEADERS: Francesco Camnasio, Maurizio De Pellegrin, Giuseppe Gioia, Crispino
Grispigni, Eliseo Mainetti
RESEARCHER: Alessandro Rubinacci
PHYSICIANS: Arianna Banfi, Erica Bulgheroni, Carlo Maria Castoldi, Alessandro De Ponti, Dario
Fracassetti, Valerj Maltsev, Davide Mandelli, Umberto Mezzadri, Gianluigi Moro, Marco Ometti,
Paola Rivoltini, Matteo Vitali
RESIDENTS: Laura Mangiavini, Alessandro Pozzi
POST-DOCTORAL FELLOW: Daniela Deponti
Gastroenterology-Endoscopy
HEAD OF UNIT: Pier Alberto Testoni*
CLINICAL UNIT LEADERS: Paolo Giorgio Arcidiacono, Mario Guslandi, Sandro Passaretti, Maria Chiara
Petrone
PHYSICIANS: Giulia Martina Cavestro*, Emanuele Dabizzi, Lorella Fanti, Alberto Mariani, Edi Viale
CONSULTANT: Elena Radice
RESIDENTS: Matteo Alessandri, Milena Di Leo, Giorgia Mazzoleni, Chiara Notaristefano, Gemma
Rossi, Sabrina G. Testoni, Raffaella A. Zuppardo
FELLOWS: Marco Le Grazie, Maria Emilia Traini
Anaesthesiology
HEAD OF UNIT: Luigi Beretta*
CLINICAL UNIT COORDINATORS: Massimo Agostoni, Massimo Caldi, Eleonora Colnaghi,
Laura Comotti, Francesco Deni, Emiliano Giorgi, Daniela Giudici, Valeria Perotti
PHYSICIANS: Barbara Airaghi, Felicia Adalgisa Antonino, Tania Capocasa, Domenica Carrieri, Mariela
Decembrino, Cinzia Elisabetta De Grandis, Alessandra Garassino, Renato Meani, Alessandra
Mello, Silvia Morero, Laura Pasin, Francesca Presti, Lorenzo Quario Rondo, Raffaella Reineke,
Stefano Turi, Federico Vinciguerra
General intensive care
HEAD OF UNIT: Alberto Zangrillo*
CLINICAL UNIT LEADER: Sergio Colombo
PHYSICIANS: Paolo Federico Beccaria, Pier Carlo Bergonzi, Luca Cabrini, Carlo Leggieri, Daniela
Mamo, Elena Moizo, Giacomo Monti, Milena Mucci, Davide Salaris, Massimo Zambon
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
The Department of general and specialistic surgery comprehends the following branches: Upper
Gastrointestinal Surgery, Colorectal Surgery, Pancreas Surgery, Hepatobiliary Surgery, Bariatric Surgery,
Lymphatic Surgery, Breast Surgery, Endocrine Surgery, General Surgery, Pancreas and Kidney Transplantation Surgery, Gastroenterology & Endoscopy Procedures, Orthopaedic Surgery, Anaesthesiology
and Intensive Care Unit. The Department has three core missions: excellence clinical care, outstanding
research productivity and high level educational program imparting.
Clinical activity and Areas of excellence
The Upper Gastrointestinal Surgery Unit has a dedicated program in treating cancers and benign diseases
of the upper gastrointestinal tract. Patients are treated by a multidisciplinary team of experts. The research
277
THE CLINICAL DEPARTMENTS
program aims to improve the pre-operative workup of esophagus and stomach tumors including magnetic resonance imaging, sentinel node identification in early cancer stage and neoadjuvant chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC) in the advanced ones.
The Colorectal Surgery Unit offers the most advanced surgical and minimally invasive options not only to
eradicate the disease, but also to preserve patients’ ability to normal function. Among the programs there
are the sentinel node mapping in colorectal and anal canal cancer as well as the perioperative evaluation
of anorectal function and pelvic floor biofeedback rehabilitation method.
The Pancreatic Surgery Unit presents one of the highest surgery volume in Europe with more than 160
pancreatic resections performed per year. In order to treat the post-surgical diabetes, secondary to total
pancreatectomy, there is an active program of islet autotransplantation.
In the Hepatobiliary Surgery Unit the activities are mainly focused on hepato-biliary tumors and chronic
liver diseases, including primary and metastatic liver tumors, benign and malignant diseases of the biliary
tract, acute and chronic hepatitis. Concerning the Hepatic Surgery the unit is a leading reference in our
country for liver resections, performing about 170 liver resection per year. A clinical program of laparoscopic liver surgery has been started on January 2007, being at the moment the most active program in
Italy.
Data regarding the Bariatric Surgery reveals a successful activity in the past years. The current program
foresees an activity increase, with special interest to the obese diabetic patient and the metabolic surgery.
Lymphatic Surgery: the primary and secondary lymphoedema surgical therapy finds in the lympho-venous
anastomosis as well as in the lymphatic grafting a reliable procedure.
In the Breast Surgery Unit the International Standard of Excellence stated by EUSOMA (European Society of Mastology) is applied. Following this criteria, 300 new malignant cases per year are enrolled and
more than 2000 patients per year are treated in the unit.
The Endocrine Surgery Unit treats endocrine tumors in children and adults. Surgeons working in this section employ cutting edge technology, includ ing minimally invasive parathyroid surgery with intraoperative
parathormone (PTH) assay determination, and laparoscopic adrenalectomy.
The clinical activity of Transplant Surgery Unit includes the following programs: Simultaneous Pancreas
and Kidney Transplantation and Pancreas Alone Transplantation in insulin dependent diabetes mellitus
(IDDM) patients; double kidney transplantation from marginal donors; laparoscopic living donor nephrectomy; islet transplantation.
The clinical activity of the Gastroenterology and Gastrointestinal Endoscopy Unit includes four main sections: clinical gastroenterology and hepatology, gastrointestinal and pancreatic biliary endoscopy, ultrasound endoscopy, and digestive motility. The unit is a tertiary referral center for therapeutic pancreatic
biliary and gastrointestinal tract endoscopy, as well as for endoscopic ultrasound, diagnosis and treatment
of motility disorders (mainly esophagus and rectum), and pancreatic diseases. Advanced endoscopic
procedures, as the endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasound,
and therapeutic gastrointestinal tract procedures are carried out under deep sedation and anesthesiologist assistance; two anesthesiologists are involved daily in two operatory rooms.
The Orthopaedic Surgery Unit cares for all injuries and diseases of the musculoskeletal system. The unit
provides subspecialty clinics in the specific areas of major joint reconstruction, sport medicine, paediatric
orthopaedics, foot, hand, spine, trauma oncology, reconstructive microsurgery, and rehabilitation.
The clinical activity of the Orthopaedics and Traumatology Unit aims to cover all the needs related to traumatic, degenerative, oncologic, infectious and metabolic aspects of the musculoskeletal system. The
spine surgery, the shoulder and elbow surgery, the treatment of the degenerative disease of the joints,
the pelvis surgery, the diagnosis and treatment of the pathologies of the bone metabolism represent areas
of distinction of the Orthopaedics and Traumatology Unit. The Orthopaedics and Traumatology Unit has
also an intense basic research activity with the Laboratory for Tissue Engineering and Biomaterials.
The Anesthesiology and Intensive Care Unit reflects the comprehensive effort of a team of anesthesia
physicians, nurses, and staff engaged in the advanced patient care. Preadmission diagnosis and staging program focus on decrease in the hospital stay. The main fields of research are: medical emergency
team; non invasive ventilation in innovative fields; percutaneous tracheostomy in difficult cases; activated
or Zymogen Protein C in sepsis; use of simulation in medical training; extracorporeal support in acute respiratory distress syndrome (ARDS) patients (in particular in influenza A H1N1 related ARDS).
The team publishes an international journal “Heart, Lung and Vessels”, freely available on www.itacta.org.
THE CLINICAL DEPARTMENTS
Fields of research
The Department of Surgery has a long and distinguished history of surgical research, nationally and internationally recognized. Unique clinical trials are offered for a variety of surgical diseases, giving life expectancy to patients with critical illness who were once considered untreatable. The research mission is
to enhance new scientific knowledge to surgically related disease and to provide outstanding scientific
training for future surgeons and surgical scientists. The key focus of the Department of Surgery is the development and application of molecular/genetic biomarkers for the diagnosis, prognosis and prediction
of treatment response of the digestive system. The primary objectives are: 1) to be a reference to surgical research; 2) to help develop new applications to clinical care; and 3) to provide outstanding research
training for surgical residents and surgical scientists.
Gianfranco Ferla
Selected publications
Balzano, G; Maffi, P; Nano, R; Zerbi, A; Venturini, M; Melzi, R; Mercalli, A; Magistretti, P; Scavini, M; Castoldi, R; Carvello, M; Braga, M; Del Maschio, A; Secchi, A; Staudacher, C; Piemonti, L. Extending indications for islet autotransplantation in pancreatic surgery. Ann. Surg.: 2013;
258(2): 210-218 - Article
Bolamperti, S; Mrak, E; Moro, G; Sirtori, P; Fraschini, G; Guidobono, F; Rubinacci, A; Villa, I.
17β-Estradiol positively modulates growth hormone signaling through the reduction of SOCS2 negative feedback in human osteoblasts. Bone: 2013; 55(1): 84-92 - Article
Masci, E; Viale, E; Notaristefano, C; Mangiavillano, B; Fiori, G; Crosta, C; Dinelli, M; Maino, M;
Viaggi, P; Della Giustina, F; Teruzzi, V; Grasso, G; Manes, G; Zambelli, S; Testoni, PA. Endoscopic
mucosal resection in high- and low-volume centers: a prospective multicentric study. Surg. Endosc.:
2013; 27(10): 3799-3805 - Article
Mukenge, S; Negrini, D; Catena, M; Ratti, F; Dosio, F; Paesano, P; Rigatti, P; Ferla, G. Development of functionally patent lymphatic meshes in postsurgical long-term resolution of peripheral
secondary lymphedema. Journal of Vascular Surgery: Venous and Lymphatic Disorders: 2013; 1(3):
280-288 - Article
Pecorelli, N; Braga, M; Doglioni, C; Balzano, G; Reni, M; Cereda, S; Albarello, L; Castoldi, R;
Capretti, G; Di Carlo, V. Preoperative Chemotherapy Does Not Adversely Affect Pancreatic Structure and Short-Term Outcome after Pancreatectomy. J. Gastrointest. Surg.: 2013; 17(3): 488-493 Article
Ratti, F; Cipriani, F; Ferla, F; Catena, M; Paganelli, M; Aldrighetti, LAM. Hilar cholangiocarcinoma: Preoperative liver optimization with multidisciplinary approach. Toward a better outcome. World
J. Surg.: 2013; 37(6): 1388-1396 - Article
Testoni, PA; Notaristefano, C; Di Leo, M; Vailati, C; Mazzoleni, G; Viale, E. High-definition with iScan gives comparable accuracy for detecting colonic lesions by non-expert and expert endoscopists. Dig. Liver Dis.: 2013; 45(6): 481-486 - Article
Vignali, A; De Nardi, P; Ghirardelli, L; Di Palo, S; Staudacher, C. Short and long-term outcomes
of laparoscopic colectomy in obese patients. World J. Gastroenterol.: 2013; 19(42): 7405-7411 Article
Vignali, A; Ghirardelli, L; Di Palo, S; Orsenigo, E; Staudacher, C. Laparoscopic treatment of advanced colonic cancer: A case-matched control with open surgery. Colorectal Dis.: 2013; 15(8):
944-948 - Article
279
HEAD AND NECK
DEPARTMENT
Head of Department:
Luigi Beretta*
DEPARTMENT AREA COORDINATORS: Antonio Dell’Acqua, Marco Gemma, Susanna Piccoli, Sandra
Pieralli, Claudio Righi, Francesco Scomazzoni
Head and neck anaesthesia and neurointensive care
HEAD OF UNIT: Luigi Beretta*
CLINICAL UNIT LEADERS: Silvano Cozzi, Cristina Mattioli
CLINICAL UNIT COORDINATORS: Antonio Dell’Acqua, Marco Gemma, Susanna Piccoli
PHYSICIANS: Fabio Bernasconi, Maria Rosa Calvi, Marco Cerri, Antonella Cipriani, Assunta De Vitis,
Cristina Frascoli, Luigi Gioia, Elisabetta Grandi, Karin Iemi, Maurizio Mungo, Alfredo Ravizza,
Francesco Ruggieri, Luisa Sacchi
RESIDENT: Massimiliano Greco
Neuroradiology
HEAD OF UNIT: Andrea Falini*
CLINICAL UNIT LEADERS: Nicoletta Anzalone, Cristina Baldoli, Sandra Pieralli, Claudio Righi, Letterio
Salvatore Politi, Franco Simionato
PHYSICIANS: Simonetta Gerevini, Silvia Pontesilli, Francesco Scomazzoni, Roberta Scotti, Paolo
Vezzulli
Ophthalmology
HEAD OF UNIT: Francesco Bandello*
CLINICAL UNIT LEADER: Francesco Fasce
CLINICAL UNIT COORDINATORS: Gianluigi Bolognesi, Luisa Pierro
PHYSICIANS: Maurizio Battaglia Parodi, Paolo Bettin, Marco Codenotti, Antonio Giordano Resti, Ugo
Introini, Rosangela Lattanzio, Francesco Loperfido, Gisella Maestranzi, Giulio Modorati
CONSULTANTS: Nicola Baccelli, Piero Barboni, Elena Bruschi, Maria Lucia Cascavilla, Carlo Ciampi,
Umberto De Benedetto, Federico Di Matteo, Marina Fiori, Maddalena Forti, Marco Gagliardi,
Matteo Ghidoni (until March 2013), Silvia Giatsidis, Lauretta Guarisco, Francesca Legorini, Angela
Malegori, Maria Pia Manitto, Elisabetta Martina, Paolo Mauceri, Elisabetta Miserocchi, Veronica
Odazio, Matteo Prati, Giuseppe Querques, Andrea Ramoni, Carmen Rojo, Alessandra Spinelli,
Monica Stoppani, Ilaria Zucchiatti
RESIDENTS: Luigi Berchicci**, Ingrid Bianchi**, Giuseppe Casalino**, Giulia Corradetti**, Claudia Del
Turco**, Giovanni Fogliato**, Lorenzo Iuliano**, Karl Anders Knutsson**, Carlo La Spina**, Jacopo
Milesi**, Davide Panico**, Lea Querques**, Giacinto Triolo **
TECHNICIANS: Giorgio Alto, Adriana Angiolini, Alessio Buzzotta, Silvia Giganti (until March 2013), Silvia
Marcaggi (since June 2013), Antonella Ribecca
THE CLINICAL DEPARTMENTS
Cornea and ocular surface Unit
HEAD OF UNIT: Paolo Rama
CONSULTANTS: Oriella Ambrosio, Giulio Ferrari, Federica Ferrario, Chiara Insacco, Stanislav Matuska,
Giorgio Paganoni, Elena Scandola, Maurizia Viganò
TECHNICIANS: Gloria Badin, Enrico Delfino
Otorhinolaryngology Unit
HEAD OF UNIT: Mario Bussi*
PHYSICIANS: Stefano Bondi, Leone Giordano, Francesca Lira Luce, Lucia Oriella Piccioni, Roberto
Teggi, Matteo Trimarchi
CONSULTANTS: Giulia Danè, Fabrizio Ferrario, Omar Gatti, Francesca Palonta, Rosaria Taverna
RESIDENTS: Matteo Biafora, Davide Di Santo, Francesco Pilolli, Daniela Sarandria, Salvatore Toma
SPEECH THERAPISTS: Daniela Gherner, Barbara Ramella
TECHNICIAN: Federica Beltrando
Neurosurgery
HEAD OF UNIT: Pietro Mortini*
CLINICAL UNIT LEADERS: Stefania Acerno, Camillo Ferrari Da Passano, Alberto Franzin, Marco Losa,
Carlo Mandelli, Aleandro Rocca
PHYSICIANS: Lina Raffaella Barzaghi, Nicola Boari, Lorenzo Gioia, Marzia Medone, Micol Valle
PHD STUDENT: Filippo Gagliardi**, Silvia Snider **
RESIDENTS: Michele Bailo, Jody Capitanio, Andrea Cavalli , Elena Colombo, Jaime Mandelli, Lucio
Aniello Mazzeo, Pietro Panni, Luca Ruggeri, Giorgio Spatola, Alfio Spina
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
The Head and Neck Department integrates the clinical and research activities of six clinical “operative
units” dedicated to pathology of: head and neck, auditory system, Central Nervous System (brain and
spinal cord), visual system.
Clinical activity and areas of excellence
From diagnosis to treatment, the areas of clinical excellence of the Department are:
Advanced neuroradiological techniques
Four high field magnetic resonance units (three 1.5T and one 3.0T MR) perform more than 13.000 MRI
per year in children and adults. Presurgical functional studies (activation, tractography) are performed on
a regular basis for surgery of brain gliomas. Advanced MR techiniques are routinely applied in cerebrovascular diseases, in the main neurodegenerative conditions such as AD, FTD and ALS and in inflammatory diseases. Pediatric MRI studies are performed in fetuses at risk, premature newborns, infants and
children, both on an outpatient basis in sedated or awake children and in emergency and inpatient basis.
Considerable advances have been performed in the field of Peripheral Nervous System imaging. High resolution and advanced MR techniques are used in the evaluation of orbital and optic nerve diseases. Interventional Neuroradiology addresses endovascular treatment of aneurysms, arteriovenous malforma
tions of the brain and spinal cord, fistulae, carotid stenosis. A wide variety of coils, stents and different
types of glue are in regular routine use. All procedures are performed in strict consultation and cooperat
ion with neurosurgery and neurointensive care units.
281
THE CLINICAL DEPARTMENTS
Neurosurgery
The clinical hallmarks of neurosurgery are:
• pituitary and base of the skull tumors. The treatment of pituitary lesion is coordinated with the clinicoendocrinological support available within the department unit. Brain gliomas are operated with the support of functional MRI studies and tractography when needed and are followed in cooperation with
neurooncology for chemiotherapy and radiotherapy units. Aggressive and extensive skull base tumors
are operated in cooperation with otolaryngology department.
• Radiosurgery is performed on a wide range of lesions from brain AVM’s to skull base tumors and brain
metastasis with a very active gamma knife up to date equipment operated on a multidisciplinary basis.
Spine surgery and peripheral nervous system surgery are also performed.
Otolaryngology
The unit is characterized by a very intense surgical activity mainly addressed to neck malignancies (tumors
of the larynx, pharynx, thyroid), paranasal sinuses, oropharyngeal cavity, base of the skull. Rehabilitation
of patients submitted to laryngectomy and evaluation and treatment of patient with dis turbed vestibular
system and vertigo are among the non surgical clinical activities.
Ophtalmology
Organised in two vision units, one of which dedicated to the cornea and ocular surface and the other one
to all the other fields of ophthalmology: pediatric ophthalmology, retinal surgery, ocular oncology with a
particular interest in orbital lymphomas and uveal melanoma treatment with Gamma Knife radiosurgery,
ocular immunology, advanced diagnostic imaging with evaluation of nerve fiber layer thickness and retinal ganglion cells in the development of epiretinal membrane. Neurophthalmology is particularly active in
studying and treating inflammatory and hereditary optic neuropathies.
Neurointensive Care
The neurointensive care unit provides support to the surgical activity of all the units of the department, neurosurgery, ophthalmology, otolaryngology and of the interventional procedures in Neuroradiology as well
as sedation of children and adults for diagnostic neuroradiological procedures. Treatment of comatose
patients and of severe brain trauma cases is one of the fields of excellence of the unit.
Luigi Beretta
Selected publications
Battaglia Parodi, M; Iacono, P; Papayannis, A; Kontadakis, SD; Cascavilla, M; Pierro, L; Gagliardi, M; Bandello, F. Intravitreal ranibizumab for pigment epithelium detachment with subfoveal
occult choroidal neovascularization: A prospective 24-month case series. Am. J. Ophthalmol.:
2013; 155(1): 103-108 - Article
Bondi, S; Limardo, P; Toma, S; Bussi, M. Non-vestibular head and neck schwannomas: a 10year experience. Eur. Arch. Oto-Rhino-Laryngol.: 2013; 270(8): 2365-2369 - Article
Codenotti, M; Fogliato, G; Iuliano, L; Querques, G; Maestranzi, G; Prati, M; Ramoni, A; De
Benedetto, U; Bandello, F. Influence of intraocular tamponade on unintentional retinal displacement after vitrectomy for rhegmatogenous retinal detachment. Retina: 2013; 33(2): 349-355 - Article
Fanti, L; Agostoni, M; Gemma, M; Rossi, G; Azzolini, ML; Viale, E; Guslandi, M; Beretta, L;
Testoni, PA. Two dosages of remifentanil for patient-controlled analgesia vs. meperidine during
colonoscopy: A prospective randomized controlled trial. Dig. Liver Dis.: 2013; 45(4): 310-315 - Article
Filippi, M; Agosta, F; Scola, E; Canu, E; Magnani, G; Marcone, A; Valsasina, P; Caso, F; Copetti, M; Comi, G; Cappa, SF; Falini, A. Functional network connectivity in the behavioral variant of
frontotemporal dementia. Cortex: 2013; 49(9): 2389-2401 - Article
THE CLINICAL DEPARTMENTS
Filippi, M; Rocca, MA; Bastianello, S; Comi, G; Gallo, P; Gallucci, M; Ghezzi, A; Marrosu, MG;
Minonzio, G; Pantano, P; Pozzilli, C; Tedeschi, G; Trojano, M; Falini, A; De Stefano, N. Guidelines
from The Italian Neurological and Neuroradiological Societies for the use of magnetic resonance imaging in daily life clinical practice of multiple sclerosis patients. Neurol. Sci.: 2013; 34(12): 20852093 - Review
Mortini, P; Gagliardi, F; Boari, N; Losa, M. Surgical strategies and modern therapeutic options in
the treatment of craniopharyngiomas. Crit. Rev. Oncol. Hematol.: 2013; 88(3): 514-529 - Review
Mortini, P; Gagliardi, F; Boari, N; Roberti, F; Caputy, AJ. The Combined Interhemispheric Subcommissural Translaminaterminalis Approach for Large Craniopharyngiomas. World Neurosurg.:
2013; 80(1-2): 160-166 - Review
Pellegrini, G; Rama, P; Matuska, S; Lambiase, A; Bonini, S; Pocobelli, A; Colabelli, RG; Spadea,
L; Fasciani, R; Balestrazzi, E; Vinciguerra, P; Rosetta, P; Tortori, A; Nardi, M; Gabbriellini, G; Traverso, CE; Macaluso, C; Losi, L; Percesepe, A; Venturi, B; Corradini, F; Panaras, A; Di Rocco, A; Guatelli, P; De Luca, M. Biological parameters determining the clinical outcome of autologous cultures
of limbal stem cells. Regen. Med.: 2013; 8(5): 553-567 - Article
Rama, P; Knutsson, KA; Razzoli, G; Matuska, S; Viganò, M; Paganoni, G. Deep anterior lamellar keratoplasty using an original manual technique. Br. J. Ophthalmol.: 2013; 97(1): 23-27 - Article
Sigurtà, A; Zanaboni, C; Canavesi, K; Citerio, G; Beretta, L; Stocchetti, N. Intensive care for pediatric traumatic brain injury. Intensive Care Med.: 2013; 39(1): 129-136 - Article
Trimarchi, M; Bussi, M; Sinico, RA; Meroni, P; Specks, U. Cocaine-induced midline destructive lesions - an autoimmune disease?. Autoimmun. Rev.: 2013; 12(4): 496-500 - Review
283
DEPARTMENT
INFECTIOUS DISEASESOF
Head of Department:
Adriano Lazzarin*
DEPARTMENT AREA COORDINATORS: Nicola Gianotti, Paolo Scarpellini
Infectious diseases
HEAD OF UNIT: Adriano Lazzarin*
CLINICAL UNIT LEADERS: Antonella Castagna, Massimo Cernuschi, Paolo Scarpellini, Giuseppe
Tambussi, Caterina Uberti-Foppa
RESEARCHERS: Laura Galli, Lucia Lopalco, Giulia Morsica, Claudia Pastori
PHYSICIANS: Paola Cinque, Anna Danise, Luca Fumagalli, Nicola Gianotti, Monica Guffanti, Myriam
Maillard, Silvia Nozza
CONSULTANTS: Laura Alagna, Simona Bossolasco, Barbara Castiglioni, Giovanni Gaiera, Andrea
Galli, Hamid Ibrahim Hasson, Flavia Salmaso, Stefania Salpietro, Vincenzo Spagnuolo, Chiara
Tassan Din
RESIDENTS: Sabrina Bagaglio, Alessia Carbone**, Stefania Chiappetta**, Francesca Ferretti**, Valeria
Longo, Marco Merli**, Emanuela Messina**, Chiara Oltolini**, Manuela Pogliaghi**, Marco Ripa**
TECHNICIAN: Manuela Testa
RESEARCH NURSES: Alba Bigoloni, Liviana Della Torre, Concetta Vinci
STUDY COORDINATORS: Elisabetta Carini, Maria Rita Parisi
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
The activity of the Department of Infectious Diseases is organized in five Functional Units (Ordinary
Admission, Day-Hospital, HIV-Infected Outpatient Service, Infectious Diseases Consultancy Service for
the whole Hospital, Experimental Therapies) and two Coordination Areas (Quality and Information Technology). The Department includes the Admission Unit with 34 beds (26 of which currently active), the DayHospital Unit with 2 beds, 13 rooms for outpatient evaluation also including gastroenterology and
fibroscan examination.
Clinical activity and Areas of excellence
These include HIV, HBV/HCV and central nervous system (CNS) infections. Management of HIV infection includes both in-hospital and outpatient care, with 4700 patients currently being followed (approximately 90% on treatment with antiretroviral drugs). The Department also follows 860 HIV-infected patients
with HBC or HCV infection, many of them treated with standard or experimental therapies and it is an active reference centre for CNS infections, particularly JCV-related progressive multifocal leukoen-
THE CLINICAL DEPARTMENTS
cephalopathy (PML). Outpatient services have also been set for TB, tropical diseases and travel medicine, and following patient hospital discharge.
The Department collaborates with the Hospital Infections Committee, to survey incidence and implement
diagnostic and treatment guidelines for management of infectious diseases, and with the Hospital Pharmacy and the Microbiology Laboratory within the Antimicrobial Management Program, on control of quality and appropriateness of antimicrobials prescriptions in hospital.
Fields of research
The Management and ARV therapy of HIV infection Clinical Research Group is involved in the conduction and coordination of national and international industry sponsored phase III and IV clinical trials contributing to the registration of new antiretroviral compounds. In addition, they have coordinated
investigator-driven, no-profit clinical studies, including on salvage strategies and simplification treatments,
such as monotherapy with protease inhibitors. The Unit also carries on observational and cohort studies
through the HIV database, which contains information from 8800 patients and collaborates with national
and international networks of HIV cohorts (ICONA, ARCA, NEAT, EuroSida, D:A:D, COHERE, EURO
CHAVI). These focus on clinically relevant areas, including long-term comorbidities associated with HIV
infection and antiretroviral treatment, such as diabetes, cancer and osteoporosis.
The Vaccine and Immunotherapy Clinical Research Group (CSQ/Certiquality/ISO 9001:2000 accreditation), with a staff well trained in the immunology and infectious diseases fields and experienced in the conduction of clinical trials, carries out preventive, therapeutic, and vaccine trials: amongst vaccine trials, VIU
is conducting studies in both HIV (Canaripox plus Remune vaccination in acute HIV infection, anti-TAT
phase I and II studies, Bionor CT-BI vacc-4X2007/01) and non- HIV field (Novartis seasonal flu, and H5N1
vaccination in immunocompromised host).
Clinical trials are also the main activity of the Hepatotropic Viruses Clinical Research Group. Trials have
included phase III studies in patients with HCV monoinfection or HIV/HCV coinfection using new directacting antiviral agents in combination with standard treatments, but also interferon-free regimens. Clinical laboratory research has moved in parallel with treatment advances by setting up methodologies for
detection and interpretation of resistance to new anti- HCV drugs.
Studies on CNS infections (Neurovirology Clinical Research Group) have involved both laboratory and clinical investigations aiming to optimize disease management by identification and validation of diseases
biomarkers. Main research areas have been HIV CNS infection and PML. Studies on HIV encephalopathy have assessed the frequency of neurocognitive impairment in treated patients, and correlates of selective HIV replication in CNS. PML studies have focused on viral and immune determinants of PML,
including sequencing of key JCV regions and studies on B-cell and T-cell responses against specific
JCV epitopes.
The Department is also involved in programs in concert with HIV patients’ associations, aiming to improve
early diagnosis and management of HIV infection and its complications. These have included the free and
anonymous administration of salivary test for HIV and HCV, an internal counseling service and structured
programs of physical activity.
The Department Director is the National Coordinator of the Healthy Ministry Italian Guidelines on the use
of antiretroviral drugs and diagnostic-clinical management of persons with HIV-1 infection. Members of
the Department are involved as committee members in the Italian guidelines on HIV infection, the European AIDS Clinical Society Guidelines for treatment of HIV infected adults and the NIH-CDC HIVMA/IDSA
Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents.
The Department organizes residential stages in this field for doctors coming from all Italy.
In 2013 more than 40 papers have been published in international scientific journals.
Adriano Lazzarin
285
THE CLINICAL DEPARTMENTS
Selected publications
Bagaglio, S; Messina, E; Uberti-Foppa, C; Merli, M; Della Torre, L; Lazzarin, A; Hasson, H;
Morsica, G. Reversion of naturally occurring high-level resistance mutations to NS3 protease inhibitors in two treatment-naive individuals infected with hepatitis C virus. J. Antimicrob. Chemother.:
2013; 68(6): 1448-1450 - Letter
Canducci, F; Ceresola, ER; Saita, D; Castagna, A; Gianotti, N; Underwood, M; Burioni, R; Lazzarin, A; Clementi, M. In vitro phenotypes to elvitegravir and dolutegravir in primary macrophages
and lymphocytes of clonal recombinant viral variants selected in patients failing raltegravir. J. Antimicrob. Chemother.: 2013; 68(11): 2525-2532 - Article
Clifford, DB; Nath, A; Cinque, P; Brew, BJ; Zivadinov, R; Gorelik, L; Zhao, Z; Duda, P. A study of
mefloquine treatment for progressive multifocal leukoencephalopathy: Results and exploration of
predictors of PML outcomes. J. Neurovirol.: 2013; 19(4): 351-358 - Article
Eron, JJ; Clotet, B; Durant, J; Katlama, C; Kumar, P; Lazzarin, A; Poizot-Martin, I; Richmond, G;
Soriano, V; Ait-Khaled, M; Fujiwara, T; Huang, J; Min, S; Vavro, C; Yeo, J; for the VIKING Study
Group. Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant
HIV type 1 infection: 24-Week results of the VIKING study. J. Infect. Dis.: 2013; 207(5): 740-748 Article
Eron, JJ; Cooper, DA; Steigbigel, RT; Clotet, B; Gatell, JM; Kumar, PN; Rockstroh, JK; Schechter,
M; Markowitz, M; Yeni, P; Loutfy, MR; Lazzarin, A; Lennox, JL; Strohmaier, KM; Wan, H; Barnard,
RJ; Nguyen, BY; Teppler, H; for the BENCHMRK Study Teams. Efficacy and safety of raltegravir
for treatment of HIV for 5 years in the BENCHMRK studies: final results of two randomised, placebocontrolled trials. Lancet Infect. Dis.: 2013; 13(7): 587-596 - Article
Ganor, Y; Drillet-Dangeard, AS; Lopalco, L; Tudor, D; Tambussi, G; Delongchamps, NB; Zerbib, M;
Bomsel, M. Calcitonin gene-related peptide inhibits langerhans cell-mediated HIV-1 transmission. J.
Exp. Med.: 2013; 210(11): 2161-2170 - Article
Pensieroso, S; Galli, L; Nozza, S; Ruffin, N; Castagna, A; Tambussi, G; Hejdeman, B; Misciagna, D; Riva, A; Malnati, M; Chiodi, F and Scarlatti, G. B-cell subset alterations and correlated factors in HIV-1 infection. AIDS: 2013; 27(8): 1209-1217 - Article
Rubenstein, JL and Wong, VS and Kadoch, C; Gao, HX; Barajas, R; Chen, L; Josephson, SA;
Scott, B; Douglas, V; Maiti, M; Kaplan, LD; Treseler, PA; Cha, S; Hwang, JH; Cinque, P; Cyster, JG;
Lowell, C. CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma. Blood:
2013; 121(23): 4740-4748 - Article
Spagnuolo, V and Travi, G; Galli, L; Cossarini, F; Guffanti, M; Gianotti, N; Salpietro, S; Lazzarin, A; Castagna, A. Clinical, virologic, and immunologic outcomes in lymphoma survivors and in
cancer-free, HIV-1-infected patients: A matched cohort study. Cancer: 2013; 119(15): 2710-2719 Article
The SPARTAC Trial Investigators. Short-course antiretroviral therapy in primary HIV infection. N.
Engl. J. Med.: 2013; 368(3): 207-217 - Article
MATERNAL AND CHILD HEALTH
DEPARTMENT
Head of Department:
Giuseppe Chiumello*
DEPARTMENT AREA COORDINATORS: Alessandro Aiuti, Riccardo Bonfanti, Maria Pia Guarneri
Pediatrics and neonatology
HEAD OF UNIT: Giuseppe Chiumello
CLINICAL UNIT LEADERS: Graziano Barera, Franco Meschi, Gianni Russo, Giovanna Weber*
PHYSICIANS: Valentina Biffi, Riccardo Bonfanti, Maddalena Bove, Stefania Di Candia, Gisella
Garbetta, Sara Osimani, Antonella Poloniato, Gabriella Pozzobon, Andrea Rigamonti, Rosanna
Rovelli, Paola Sgaramella, Maria Cristina Vigone
RESEARCHER: Stefano Mora
RESIDENTS: Roseila Battaglino**, Clara Bonura**, Silvana Caiulo**, Bruna Cammarata**, Patrizia
Corsin**, Chiara Damia**, Marianna Di Frenna**, Alessandra Di Lascio**, Valentina Donghi**, Valeria
Favalli**, Maria Piera Ferrarello**, Giulio Frontino**, Moira Gianninoto**, Elena Grechi**, Silvia
Meroni**, Elena Peroni**, Sarah Rabbiosi**, Giulia Maria Tronconi**
Gynaecology and obstetrics
HEAD OF UNIT: Massimo Candiani*
CLINICAL UNIT LEADERS: Ferdinando Bombelli, Maria Teresa Castiglioni, Enrico Conti, Giorgia
Mangili, Enrico Papaleo, Daniele Spagnolo, Luca Valsecchi, Riccardo Viganò
CLINICAL UNIT COORDINATORS: Guido Candotti, Gabriella Colombo, Moreno Dindelli, Stefano
Ferrari, Stefania Luchini
RESEARCHERS: Massimo Origoni*, Stefano Salvatore*
PHYSICIANS: Giada Almirante, Luigi Caputo, Anna Cardani, Paolo Cavoretto, Patrizia De Marzi,
Davide Ferrari, Luca Gandini, Elisabetta Garavaglia, Paolo Giardina, Elena Marsiglio, Fabio Mauro,
Michela Molgora, Federica Pasi, Paola Persico, Micaela Petrone, Maria Teresa Potenza, Laura
Privitera, Emanuela Rabaiotti, Susanna Rosa, Maddalena Smid, Simona Vailati
BIOLOGISTS: Laura Corti, Lucia De Santis, Giulia Intra, Paola Panina, Elisa Rabelotti, Paola Viganò
CONSULTANTS: Rossana Cairone, Raffaella Chionna, Rossana Favia, Susanna Filippis, Fiorenza
Lagona, Silvia Maddalena, Guido Marelli, Valentina Mariotti, Mara Zanirato
RESIDENTS: Alice Bergamini**, Guia Carminati**, Diana Del Prato**, Lara Di Piazza**, Veronica
Giorgione**, Eleonora Iachini**, Annalisa Inversetti**, Jessica Ottolina**, Marta Parma**, Francesca
Pella**, Lavinia Quaranta**, Audrey Serafini**, Cristina Sigismondi**, Chiara Stefani**, Iacopo
Tandoi**
FELLOWS: Luca Pagliardini, Umberto Leone Roberti Maggiore, Ana Maria Sanchez
287
THE CLINICAL DEPARTMENTS
Pediatric immuno-hematology Unit
HEAD OF UNIT: Maria Grazia Roncarolo*
PHYSICIANS: Alessandro Aiuti, Rosa Bacchetta, Maria Pia Cicalese
PHYSICIAN SCIENTIST SENIOR: Alessandra Biffi
PHYSICIAN: Maddalena Migliavacca (since July 2013)
RESIDENTS: Federica Barzaghi**, Francesca Ferrua**, Marta Frittoli**, Mila Kalapurackal** (since July
2013), Laura Lorioli**, Sara Napolitano**, Roberta Pajno**
CHARGE NURSE: Clara Soliman
RESEARCH NURSES: Gigliola Antonioli, Miriam Casiraghi
DATA MANAGER: Laura Castagnaro (since November 2013), Sara Di Nunzio (until September 2013),
Marcella Facchini (since November 2013), Emanuela Mrak (since October 2013)
REGULATORY AFFAIRS OFFICE: Marco Bonopane
TCTO COORDINATOR: Luciano Callegaro
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
Obstetrics and gynecology Unit
The scientific and clinical activities involve:
1. Gynecological Surgery. The Unit is pilot centre for the diagnosis and treatment of endometriosis with
a multidisciplinary approach and the most advanced minimally invasive surgical techniques.
2. Reproductive Sciences. The Infertility Unit completed two multicentre randomised control clinical trials
on the efficacy of subcutaneous progesterone, and rFSH/rLH treatment on the outcome of ovulation
induction protocols. One major research focus is the identification of new genomic biomarkers involved
in controlling embryo implantation after IVF, including the HLAG antigen and its functional polymorphisms in relationship with tolerogenic cells.
3. Cancer Prevention. Two new projects have been developed in order to better deal with problems regarding fertility in female cancer patients. This collaboration between the fertility and gynecology oncology unit aims to translate these new options for preservation of fertility in oncological patients into
clinical practice.
Pediatrics and neonatology
Neonatology
The research activities involve:
1. Metabolic-clinical outcome of infants born preterm or from mothers with diabetes. We are studying the
effect of specific intrauterine environments on extra-uterine growth (body composition and bone mineralization).
2. Development study of the Central Nervous System. Our group co-operates with the Department of Pediatric Neuroradiology for clinical application of Diffusion Tensor Imaging and Functional MRI and their
feasibility in newborns.
Diabetes, obesity and metabolic diseases in children and adolescents
The areas research are: prevention of diabetes, technology in diabetes, genetic-metabolic studies in
neonatal insulin resistant diabetes.
In cooperation with Bambino Gesù Hospital (Rome) we are studying phenotype-genotype correlations in
insulin-resistant diabetes due to insulin receptor gene mutations and incidence of neonatal/infancy onset
diabetes in Italy. We collaborate in Trialnet primary and secondary prevention study, and with Diabetes Research Institute in evaluating the role of innate immunity in type 1 diabetes .
Clinical research regarding Prader-Willi Syndrome (PWS):
• effects of long-term GH therapy on sleep-disordered breathing and adenotonsillar hypertrophy
• prevalence of central adrenal insufficiency
THE CLINICAL DEPARTMENTS
We also studied the clinical/molecular features of patients with congenital hyperinsulinism and their parents, allowing the identification of the potential causative gene mutations.
Pediatric endocrinology
The fields of research are thyroid diseases, short stature, Congenital Adrenal Hyperplasia (CAH), Hypogonadotrophic Hypogonadism (HH) and Disorders of sex differentiation (DSD). Regarding Congenital
Hypothyroidism (CH) we collaborate with the University of Milan to assess the genetic, epigenetic and environmental factors contributing to CH.
As co-investigator of AIFA Research we investigate the influence of initial Levothyroxine dose at diagnosis on neurodevelopmental outcomes in children with CH. We also studied the response to Growth Hormone in terms of growth velocity and short term height and its correlation to genotype in Noonan patients.
We assess serum, salivary and urinary steroid profiles through LC-MS for diagnosis and follow-up of various forms of CAH. We study patients with HH from a clinical/genetic perspective. We aim to standardize pharmacologic tests execution and results interpretation in order to obtain a better diagnostic definition,
together with genetic analysis.
Pediatric immuno-hematology Unit
Clinical research involves immunological, hematological, autoimmune, lysosomal storage disorders and
other genetic diseases. Experimental therapeutic options are also offered. We performed more than 70
pediatric allogeneic stem cell transplantations for thalassemia, sickle cell anemia, primary immunodeficiencies and malignancies, in cooperation with the San Raffaele Stem Cell Programme. The Unit collaborates
with HSR-TIGET on advanced diagnosis, pathogenetic studies and development of novel therapeutic
approaches for genetic diseases, with particular regards to primary immunodeficiencies, autoimmune
diseases with known or unknown genetic defect, lysosomal storage disorders and hemoglobinopathies.
Results from long-term follow up in ADA-SCID patients treated with retroviral-mediated gene therapy confirm its efficacy and safety. Initial results of clinical trials for Metachromatic Leukodystrophy and WiskottAldrich Syndrome have shown that the infusion of transduced hematopoietic stem cells is safe and
efficacious. Patients affected by Duchenne muscular dystrophy have been treated with cell therapy and
their follow up is currently ongoing. Clinical trials of gene therapy for β-thalassemia and Mucopolisaccaridosis I are in preparation.
Giuseppe Chiumello
Selected publications
Aiuti, A; Biasco, L and Scaramuzza, S; Ferrua, F; Cicalese, MP; Baricordi, C; Dionisio, F; Calabria, A; Giannelli, S; Castiello, MC; Bosticardo, M; Evangelio, C; Assanelli, A; Casiraghi, M;
Di Nunzio, S; Callegaro, L; Benati, C; Rizzardi, P; Pellin, D; Di Serio, C; Schmidt, M; Von Kalle, C;
Gardner, J; Mehta, N; Neduva, V; Dow, DJ; Galy, A; Miniero, R; Finocchi, A; Metin, A; Banerjee, P;
Orange, J; Galimberti, S; Valsecchi, MG; Biffi, A; Montini, E; Villa, A; Ciceri, F; Roncarolo, MG
and Naldini, L. Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich
Syndrome. Science: 2013; 341(6148): 123351 - Article
Berini, J; Spica Russotto, V; Castelnuovo, P; Di Candia, S; Gargantini, L; Grugni, G; Iughetti, L; Nespoli, L; Nosetti, L; Padoan, G; Pilotta, A; Trifiro, G; Chiumello, G; Salvatoni, A; on behalf of the Genetic Obesity Study Group of the Italian Society of Pediatric Endocrinology and Diabetology (ISPED).
Growth hormone therapy and respiratory disorders: Long-term follow-up in PWS children. J. Clin.
Endocrinol. Metab.: 2013; 98(9): E1516-E1523 - Article
Biffi, A and Montini, E; Lorioli, L; Cesani, M; Fumagalli, F; Plati, T; Baldoli, C; Martino, S; Calabria, A; Canale, S; Benedicenti, F; Vallanti, G; Biasco, L; Leo, S; Kabbara, N; Zanetti, G; Rizzo,
WB; Mehta, NA; Cicalese, MP; Casiraghi, M; Boelens, JJ; Del Carro, U; Dow, DJ; Schmidt, M;
Assanelli, A; Neduva, V; Di Serio, C; Stupka, E; Gardner, J; von Kalle, C; Bordignon, C; Ciceri,
F; Rovelli, A; Roncarolo, MG; Aiuti, A; Sessa, M; Naldini, L. Lentiviral Hematopoietic Stem Cell
Gene Therapy Benefits Metachromatic Leukodystrophy. Science: 2013; 341(6148): 1233158 - Article
289
THE CLINICAL DEPARTMENTS
Goudy, K and Aydin, D; Barzaghi, F; Gambineri, E; Vignoli, M; Mannurita, SC; Doglioni, C; Ponzoni, M; Cicalese, MP; Assanelli, A; Tommasini, A; Brigida, I; Dellepiane, RM; Martino, S; Olek,
S; Aiuti, A; Ciceri, F; Roncarolo, MG; Bacchetta, R. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin. Immunol.: 2013; 146(3): 248-261 Article
Mangili, G; Ottolina, J; Gadducci, A; Giorda, G; Breda, E; Savarese, A; Candiani, M; Frigerio, L;
Scarfone, G; Pignata, S; Rossi, R; Marinaccio, M; Lorusso, D. Long-term follow-up is crucial after
treatment for granulosa cell tumours of the ovary. Br. J. Cancer: 2013; 109(1): 29-34 - Article
Pagliardini, L; Gentilini, D; Viganò, P; Panina-Bordignon, P; Busacca, M; Candiani, M; Di Blasio,
AM. An Italian association study and meta-analysis with previous GWAS confirm WNT4,
CDKN2BAS and FN1 as the first identified susceptibility loci for endometriosis. J. Med. Genet.:
2013; 50(1): 43-46 - Article
Rabbiosi, S; Vigone, MC; Cortinovis, F; Zamproni, I; Fugazzola, L; Persani, L; Corbetta, C;
Chiumello, G; Weber, G. Congenital hypothyroidism with eutopic thyroid gland: Analysis of clinical
and biochemical features at diagnosis and after re-evaluation. J. Clin. Endocrinol. Metab.: 2013;
98(4): 1395-1402 - Article
Sanchez, AM; Giorgione, V; Viganò, P; Papaleo, E; Candiani, M; Mangili, G; Panina-Bordignon, P. Treatment with anticancer agents induces dysregulation of specific Wnt signaling pathways
in human ovarian luteinized granulosa cells in vitro. Toxicol. Sci.: 2013; 136(1): 183-192 - Article
Valle, A and Giamporcaro, GM and Scavini, M; Stabilini, A; Grogan, P; Bianconi, E; Sebastiani, G; Masini, M; Maugeri, N; Porretti, L; Bonfanti, R; Meschi, F; De Pellegrin, M; Lesma, A;
Rossini, S; Piemonti, L; Marchetti, P; Dotta, F; Bosi, E; Battaglia, M. Reduction of circulating neutrophils precedes and accompanies type 1 diabetes. Diabetes: 2013; 62(6): 2072-2077 - Article
DEPARTMENT
OF
INTERNAL AND
SPECIALISTIC MEDICINE
Head of Department:
Emanuele Bosi*
DEPARTMENT AREA COORDINATORS: Giselda Colombo, Matteo Rocco Pastore, Moreno Tresoldi
General medicine, diabetes, endocrinology and metabolic diseases
HEAD OF UNIT: Emanuele Bosi*
CLINICAL UNIT LEADERS: Gabriella Galimberti, Roberto Lanzi, Marco Federico Manzoni, Matteo
Rocco Pastore, Piermarco Piatti
PHYSICIANS: Alberto Davalli, Sabina Martinenghi, Alessandro Saibene, Maurizio Storti
RESIDENTS: Andrea Bolla**, Amelia Caretto**, Anna Dolcetta Capuzzo**, Ilaria Formenti**, Laura
Frosio**, Alessandra Gandolfi**, Tania Garito**, Chiara Molinari**, Valentina Villa**
FELLOWS: Valentina Giulia Crippa, Raffaele Di Fenza, Andrea Laurenzi, Francesca Perticone,
Alessandro Rossini, Emanuela Setola
NUTRITIONIST: Monica Marchi
TRIAL COORDINATOR: Pauline Grogan
RESEARCH NURSE: Eleonora Bianconi
Clinical transplantation
HEAD OF UNIT: Antonio Secchi*
CLINICAL UNIT LEADERS: Rossana Caldara, Ennio La Rocca, Paola Maffi
CONSULTANTS: Chiara Gremizzi, Vera Paloschi
RESIDENTS: Francesca D’Addio, Silvia Foti
RESEARCH NURSE: Barbara Pontiroli
General medicine, clinical immunology and rheumatology
HEAD OF UNIT: Maria Grazia Sabbadini*
CLINICAL UNIT LEADERS: Giselda Colombo, Luisa Praderio, Moreno Tresoldi
PHYSICIANS: Enrica P. Bozzolo, Lorenzo Dagna*, Angelo A. Manfredi*, Massimo Memoli, Patrizia
Rovere-Querini*, Chiara Salmaggi, Nicoletta Saporiti, Raffaella Scotti, Magda Vecellio
CONSULTANTS: Patrizia Aiello, Elena Baldissera, Teresa D’Aliberti, Mirta Tiraboschi
RESIDENTS: Nicola Bettera, Margherita Bevilacqua, Andrea Duca, Luca Ferrante, Andrea Segalini,
Cristina Sorlini, Enrico Tombetti
291
THE CLINICAL DEPARTMENTS
Nephrology and dialysis
HEAD OF UNIT: Donatella Spotti
CLINICAL UNIT LEADERS: Paolo Manunta*, Giorgio Slaviero, Giuseppe Vezzoli
PHYSICIANS: Teresa Arcidiacono, Chiara Lanzani, Marco Melandri, Rita Quartagno, Maria Teresa
Sciarrone Alibrandi, Marco Simonini
RESIDENTS: Guido Gatti**, Lino Merlino**, Marina Nuzzo**, Simona Pozzoli**, Stefano Tentori**,
Francesco Trevisani**
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
The Department of Internal Medicine incorporates all the areas and clinical activities of General and
Specialized Medicine of the San Raffaele Hospital and Scientific Institute. Within the Department, physicians, nurses, technicians, students and volunteers are dedicated to patients clinical care, with a continuum of treatments encompassing preventive medicine, acute care, palliative therapies and rehabilitation.
The objective of the Department is to integrate clinical care, research and education with the aim of assisting patients at the best of current medical knowledge and technological expertise.
Clinical activity and Areas of excellence
The Department of Internal Medicine is composed of four inpatient Clinical Units, a Day Hospital Service
and many Outpatient Clinics covering General Medicine and the medical specialties of Allergology, Clinical Immunology, Clinical Transplantation, Diabetes, Dialysis, Endocrinology, Hypertension, Metabolic Diseases, Nephrology, Nutrition and Rheumatology. Moreover, the Department of Internal Medicine works
in close interaction with the Emergency Department, representing the main structure for hospitalization of
patients presenting at the Emergency Medicine. The Department of Internal Medicine offers a complete
range of teaching for students at the Medical School and hosts the Post Graduate Medical Schools of
Allergology and Clinical Immunology, Endocrinology, Nephrology and Emergency Medicine, being also
recognized as a centre of excellence in these specific fields.
Fields of research
Integration between clinical care and research is a general theme across the Department. Relevant activities include: phase II/III clinical trials on novel pharmacological treatments and diagnostic tools in the
fields of diabetes, rheumatoid arthritis, metabolism, hypertension, cardiovascular and immune-mediated
diseases; and some important projects of translational medicine in the fields of islet transplantation and
immunotherapies of type 1 diabetes and other autoimmune diseases. The Department is embedded in
a remarkable clinical and scientific environment at San Raffaele, which offers unique opportunities for interdisciplinary collaboration and translational research. The scientific production by physicians and clinical investigators from the Department is remarkable, with internationally recognized areas of excellence
in diabetes and metabolism, clinical immunology, hypertension, islet and pancreas transplantation.
Emanuele Bosi
Selected publications
Bosi, E; Bax, G; Scionti, L; Spallone, V; Tesfaye, S; Valensi, P; Ziegler, D; on behalf of the FREMS
European Trial Study Group. Frequency-modulated electromagnetic neural stimulation (FREMS) as a
treatment for symptomatic diabetic neuropathy: results from a double-blind, randomised, multicentre, long-term, placebo-controlled clinical trial. Diabetologia: 2013; 56(3): 467-475 - Article
Bosi, E; Scavini, M; Ceriello, A; Cucinotta, D; Tiengo, A; Marino, R; Bonizzoni, E; Giorgino, F; on
behalf of the PRISMA STUDY GROUP. Intensive structured self-monitoring of blood glucose and
THE CLINICAL DEPARTMENTS
glycemic control in noninsulin-treated type 2 diabetes: the PRISMA randomized trial. Diabetes Care:
2013; 36(10): 2887-2894 - Article
Bozzolo, EP; Ramirez, GA; Bonavida, G; Lanzani, C; Scotti, R; Dell’Antonio, G; Baldissera, E;
Canti, V; Manfredi, AA; Rovere-Querini, P; Sabbadini, MG. Efficacy and toxicity of treatments for
nephritis in a series of consecutive lupus patients. Autoimmunity: 2013; 46(8): 537-546 - Article
Della-Torre, E; Passerini, G; Furlan, R; Roveri, L; Chieffo, R; Anzalone, N; Doglioni, C; Zardini,
E; Sabbadini, MG; Franciotta, D. Cerebrospinal fluid analysis in immunoglobulin G4-related hypertrophic pachymeningitis. J. Rheumatol.: 2013; 40(11): 1927-1929 - Letter
Dogliotti, E; Vezzoli, G; Nouvenne, A; Meschi, T; Terranegra, A; Mingione, A; Brasacchio, C; Raspini, B; Cusi, D; Soldati, L. Nutrition in calcium nephrolithiasis. J. Transl. Med.: 2013; 11: 109 - Review
Maffi, P and Balzano, G; Ponzoni, M; Nano, R; Sordi, V; Melzi, R; Mercalli, A; Scavini, M;
Esposito, A; Peccatori, J; Cantarelli, E; Messina, C; Bernardi, M; Del Maschio, A; Staudacher,
C; Doglioni, C; Ciceri, F; Secchi, A; Piemonti, L. Autologous Pancreatic Islet Transplantation in
Human Bone Marrow. Diabetes: 2013; 62(10): 3523-3531 - Article
Pierobon, ES; Sandrini, S; De Fazio, N; Rossini, G; Fontana, I; Boschiero, L; Gropuzzo, M; Gotti, E;
Donati, D; Minetti, E; Gandolfo, MT; Brunello, A; Libetta, C; Secchi, A; Chiaramonte, S; Rigotti, P.
Optimizing utilization of kidneys from deceased donors over 60 years: Five-year outcomes after implementation of a combined clinical and histological allocation algorithm. Transplant Int.: 2013; 26(8):
833-841 - Article
Vezzoli, G and Terranegra, A and Aloia, A; Arcidiacono, T; Milanesi, L; Mosca, E; Mingione, A;
Spotti, D; Cusi, D; Hou, J; Hendy, GN; Soldati, L. Decreased transcriptional activity of calciumsensing receptor gene promoter 1 is associated with calcium nephrolithiasis. J. Clin. Endocrinol.
Metab.: 2013; 98(9): 3839-3847 - Article
293
DEPARTMENT
OF
CLINICAL NEUROSCIENCE
Head of Department:
Enrico Smeraldi*
DEPARTMENT AREA COORDINATORS: Barbara Barbini, Francesco Benedetti, Maria Cristina
Cavallini, Ernestina Politi, Paolo Ronchi
General psychiatry
HEAD OF UNIT: Enrico Smeraldi*
CLINICAL UNIT LEADERS: Ernestina Politi, Paolo Ronchi
PHYSICIANS: Sara Dallaspezia, Marta Henin, Francesca Siliprandi, Laura Sforzini
PSYCHOLOGISTS: Vittoria Bottelli, Daniele Cavadini, Tomaso Siccardi, Cecilia Smeraldi
RESIDENTS: Giampiero Bottero**, Valentina Ferrari**, Antonella Rita Mastromatteo**
Clinical health psychology
HEAD OF UNIT: Lucio Sarno*
PSYCHOLOGISTS: Letizia Carnelli, Valentina Di Mattei*, Claudia Yvonne Finocchiaro, Camilla Giulia
Andrea Ghidini, Serena Giuliani, Luca Leardini, Maria Rita Milesi, Chiara Motta, Liliana Novella, Sara
Peluso, Maria Monica Ratti
RESIDENT: Stefano Clerici
Clinical psychology and psychotherapy
HEAD OF UNIT: Cesare Maffei*
CLINICAL UNIT LEADERS: Mariagrazia Movalli, Laura Vanzulli
CLINICAL UNIT COORDINATORS: Andrea Fossati*, Raffaele Visintini
CONSULTANTS: Roberta Alesiani, Silvia Boccalon, Serena Borroni, Paola Broggi, Elena Campanini,
Ilaria Carretta, Paolo Casati, Rosaria Devoti, Michela Donini, Cinzia Facchi, Marina Fiore, Nicolò
Gaj, Laura Giarolli, Salvatore La Viola, Alessandro Pieri, Sergio Premoli, Martina Testa, Roberto
Vanni, Daniele Villa
EXTERNAL RESIDENTS: Serena Artesani, Antonella Di Biase, Michela Adele Pozzi, Emanuela Roder,
Manuela Sanvito, Edoardo Vassallo
Neurology
HEAD OF UNIT: Stefano F. Cappa* (until October 2013), Sandro Iannaccone (since November 2013)
SCIENTIFIC CONSULTANT: Stefano F. Cappa*(since November 2013)
CLINICAL UNIT LEADER: Alessandra Marcone
RESEARCHERS: Jubin Abutalebi*, Nicola Canessa*, Chiara Cerami
PHYSICIANS: Maria Cristina Giusti, Valeria Golzi, Barbara Sferrazza, Michele Zamboni
PSYCHOLOGISTS: Federica Alemanno, Giada Caramatti, Valentina Esposito
THE CLINICAL DEPARTMENTS
Eating disorders
HEAD OF UNIT: Laura Bellodi*
CLINICAL UNIT LEADER: Daniela Di Molfetta, Stefano Erzegovesi
CLINICAL UNIT COORDINATOR: Maria Cristina Cavallini
PHYSICIAN: Alessandro Bernasconi
Mood disorders
HEAD OF UNIT: Cristina Colombo*
CLINICAL UNIT LEADERS: Linda Franchini, Marco Locatelli, Raffaella Zanardi
PHYSICIANS: Barbara Barbini, Francesco Benedetti, Euridice Campori, Danilo Dotoli, David Rossini
RESIDENTS: Silvia Brioschi**, Dario Delmonte**, Charlotte Desantis**, Clara Locatelli**
Psychotic disorders disease Unit
HEAD OF UNIT: Roberto Cavallaro
PHYSICIANS: Laura Bianchi, Marta Bosia**
RESIDENT: Marco Spangaro**
PSYCHOLOGIST: Margherita Bechi
Sleep disorders
HEAD OF UNIT: Luigi Ferini-Strambi*
PHYSICIANS: Alessandro Oldani, Marco Zucconi
PSYCHOLOGISTS: Vincenza Elena Castronovo, Laura Giarolli, Sara Marelli
TECHNICIANS: Massimo Antonio, Daniele Bizzozero, Elisa Dallabà, Cristina Martinelli
Out patients services (Ambulatory and day care)
HEAD OF UNIT: Enrico Smeraldi*
Alcoholism
HEADS: Enrico Smeraldi*, Cesare Maffei*
CLINICAL UNIT LEADERS: Sara Angelone, Mariagrazia Movalli
RESIDENT: Angelo Notaristefano**
Eating disorders
HEAD: Laura Bellodi*
PHYSICIAN: Cinzia Arancio
Anxiety disorders
HEAD: Laura Bellodi*
PHYSICIANS: Marco Catalano, Silvia Cocchi, Angela Gabriele
FELLOWS: Emma Fadda, Elisa Galimberti, Riccardo Martoni
Psychotic disorders
HEAD: Roberto Cavallaro
CLINICAL UNIT LEADER: Federica Cocchi
PHYSICIAN: Carmelo Guglielmino
PSYCHOLOGIST: Maria Chiara Buonocore
Personality disorders
HEAD: Cesare Maffei
CLINICAL UNIT LEADER: Raffaele Visintini
PHYSICIAN: Laura Sforzini
295
THE CLINICAL DEPARTMENTS
Mood disorders
HEAD: Cristina Colombo*
CLINICAL UNIT LEADERS: Linda Franchini, Marco Locatelli, Raffaella Zanardi
PHYSICIANS: Barbara Barbini, Francesco Benedetti, Euridice Campori, Danilo Dotoli, David
Rossini
Obsessive compulsive disorders
HEAD: Enrico Smeraldi*
PHYSICIANS: Sara Dallaspezia, Marta Henin
PSYCHOLOGISTS: Giulia Mazza, Cecilia Smeraldi
RESIDENT: Irene Vanelli**
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
The first and main committment of the Department is to define and to develop common guideline for
the clinical approach to the different aspects of behavioural disorders, according to the funding principles
of our Institution, in order to overcome the strict meaning of each symptom and to adequately consider
the nature and the whole of the individual suffering.
The public psychiatric structure is based on the model of Mental Health Department (DSM). Our department, in its psychiatric and psychological component, is based on long term therapeutical assistance,
hence resembling DSM and their mode of function, but it differs from DSM in its objectives.
In DSM, the main aim is to take care of the mental health of a community (differently defined) and it must
be addressed in terms of prevention too. Treating patients in wards dedicated to acute treatment for
strictly necessary periods and relying on ambulatory and residential/semiresidential servicesfor th remaing
part of the therapeutical process is a choice which can be considered also as a therapy in social environment (= territory, in the language of social psychiatry), that will be useful and produce mental health.
The activity of our Department is different in that it is mainly focused on the individual suffering and is addressed to the patient: the possible interest for the environment in which he lives or for his relationships
is only aimed at improving assistance and therapeutical approach to the patient, who freely chooses our
structure instead of the public one, even if located in his territory.
The relationship between these two types of Psychiatric Departments has not yet been established and
we are trying to find a different model of assistance according to the psychopathological “quality” of each
disease. Translational research is a proved reality in our department with results of basic and clinical research rapidly transferred to everyday treatment protocols. In the opposite direction clinical activity is a constant inspiration for new research with the aim to continuously ‘raise the bar’ of possible treatment efficacy,
in a virtuous circle of which the primary beneficiary is the patient.
Another innovative feature is to put together in the same Department cognitive neurology and psychiatry, since behavioural disorders are frequent and common and the same therapeutical principles can be
applied.
Clinical activity and Areas of excellence
Following the principle that expertise is based on the widest experience possible in a selected area of
treatment/research, the clinical structure relies on disease-dedicated units:
• Mood disorders
• Psychotic disorders
• Anxiety disorders
• Eating disorders
• Personality disorders
• Alcohol abuse
We have 120 beds for acute treatment and rehabilitation treatment where the therapeutical environment
in which all mental health workers operate is studied and maintained to optimize pharmacological and non
THE CLINICAL DEPARTMENTS
pharmacological treatments. The way in which treatments are delivered is in our principles the key feature for a successful therapy and is, then, a part of them.
Ambulatory and day-care activities are similarly structured as activities of the disease-dedicated units.
Fields of research
The department produces research in all the neurosciences areas encompassed by the activity of the disease-dedicated units, with the inspiring ‘leit motiv’ of getting results for personalized medicine rather than
for ‘average medicine’. This is the consequence of the strong psychiatric genetic vocation on which the
department was founded and that is easily readable in any research program and its results publication.
Areas of recognized excellence are:
• Molecular Biology and Genetics
• Brain imaging
• Clinical Psychopharmacology
• Cronobiology
• Neuropsychology
• Neurocognitive remediation and rehabilitation
Enrico Smeraldi
Selected publications
Bechi, M; Spangaro, M; Bosia, M; Zanoletti, A; Fresi, F; Buonocore, M; Cocchi, F; Guglielmino, C; Smeraldi, E; Cavallaro, R. Theory of Mind intervention for outpatients with schizophrenia.
Neuropsychol. Rehabil.: 2013; 23(3): 383-400 - Article
Benedetti, F; Bollettini, I; Barberi, I; Radaelli, D; Poletti, S; Locatelli, C; Pirovano, A; Lorenzi, C;
Falini, A; Colombo, C; Smeraldi, E. Lithium and GSK3-β promoter gene variants influence white
matter microstructure in bipolar disorder. Neuropsychopharmacology: 2013; 38(2): 313-327 - Article
Benedetti, F; Giacosa, C; Radaelli, D; Poletti, S; Pozzi, E; Dallaspezia, S; Falini, A; Smeraldi,
E. Widespread changes of white matter microstructure in obsessive-compulsive disorder: Effect of
drug status. Eur. Neuropsychopharmacol.: 2013; 23(7): 581-593 - Article
Canessa, N; Crespi, C; Motterlini, M; Baud-Bovy, G; Chierchia, G; Pantaleo, G; Tettamanti,
M; Cappa, SF. The functional and structural neural basis of individual differences in loss aversion. J.
Neurosci.: 2013; 33(36): 14307-14317 - Article
Carlotta, D; Borroni, S; Maffei, C; Fossati, A. On the relationship between retrospective childhood
ADHD symptoms and adult BPD features: The mediating role of action-oriented personality traits.
Compr. Psychiatry: 2013; 54(7): 943-952 - Article
Dauvilliers, Y; Postuma, RB; Ferini-Strambi, L; Arnulf, I; Hogl, B; Manni, R; Miyamoto, T; Oertel, W;
Fantini, ML; Puligheddu, M; Jennum, P; Sonka, K; Zucconi, M; Leu-Semenescu, S; Frauscher, B;
Terzaghi, M; Miyamoto, M; Unger, M; Desautels, A; Wolfson, C; Pelletier, A; Montplaisir, J. Family
history of idiopathic REM behavior disorder a multicenter case-control study. Neurology: 2013;
80(24): 2233-2235 - Article
Davis, LK; Yu, D; Keenan, CL; Gamazon, ER; Konkashbaev, AI; Derks, EM; Neale, BM; Yang, J;
Lee, SH; Evans, P; Barr, CL; Bellodi, L; Benarroch, F; Berrio, GB; Bienvenu, OJ; Bloch, MH; Blom,
RM; Bruun, RD; Budman, CL; Camarena, B; Campbell, D; Cappi, C; Cardona Silgado, JC; Cath,
DC; Cavallini, MC; Chavira, DA; Chouinard, S; Conti, DV; Cook, EH; Coric, V; Cullen, BA; Deforce,
D; Delorme, R; Dion, Y; Edlund, CK; Egberts, K; Falkai, P; Fernandez, TV; Gallagher, PJ; Garrido, H;
Geller, D; Girard, SL; Grabe, HJ; Grados, MA; Greenberg, BD; Gross-Tsur, V; Haddad, S; Heiman,
GA; Hemmings, SMJ; Hounie, AG; Illmann, C; Jankovic, J; Jenike, MA; Kennedy, JL; King, RA; Kremeyer, B; Kurlan, R; Lanzagorta, N; Leboyer, M; Leckman, JF; Lennertz, L; Liu, C; Lochner, C; Lowe, TL; Macciardi, F; McCracken, JT; McGrath, LM; Mesa Restrepo, SC; Moessner, R; Morgan, J;
Muller, H; Murphy, DL; Naarden, AL; Ochoa, WC; Ophoff, RA; Osiecki, L; Pakstis, AJ; Pato, MT; Pato, CN; Piacentini, J; Pittenger, C; Pollak, Y; Rauch, SL; Renner, TJ; Reus, VI; Richter, MA; Riddle,
297
THE CLINICAL DEPARTMENTS
MA; Robertson, MM; Romero, R; Rosario, MC; Rosenberg, D; Rouleau, GA; Ruhrmann, S; Ruiz-Linares, A; Sampaio, AS; Samuels, J; Sandor, P; Sheppard, B; Singer, HS; Smit, JH; Stein, DJ;
Strengman, E; Tischfield, JA; Valencia Duarte, AV; Vallada, H; Van Nieuwerburgh, F; Veenstra-VanderWeele, J; Walitza, S; Wang, Y; Wendland, JR; Westenberg, HGM; Shugart, YY; Miguel, EC;
McMahon, W; Wagner, M; Nicolini, H; Posthuma, D; Hanna, GL; Heutink, P; Denys, D; Arnold, PD;
Oostra, BA; Nestadt, G; Freimer, NB; Pauls, DL; Wray, NR; Stewart, SE and Mathews, CA and Knowles, JA and Cox, NJ and Scharf, JM. Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture. PLoS Genet.: 2013; 9(10):
e1003864 - Article
Fadda, E; Galimberti, E; Cammino, S; Bellodi, L. Smoking, physical activity and respiratory irregularities in patients with panic disorder. Riv. Psichiatr.: 2013; 48(4): 293-300 - Article
Ferini-Strambi, L. A need for new treatments in narcolepsy. Lancet Neurol: 2013; 12(11): 10391040 - Comment
Fossati, A; Krueger, RF; Markon, KE; Borroni, S; Maffei, C. Reliability and Validity of the Personality
Inventory for DSM-5 (PID-5): Predicting DSM-IV Personality Disorders and Psychopathy in Community-Dwelling Italian Adults. Assessment: 2013; 20(6): 689-708 - Article
Innocenti, I; Cappa, SF; Feurra, M; Giovannelli, F; Santarnecchi, E; Bianco, G; Cincotta, M; Rossi,
S. TMS interference with primacy and recency mechanisms reveals bimodal episodic encoding in
the human brain. J. Cogn. Neurosci.: 2013; 25(1): 109-116 - Article
Poletti, S; Radaelli, D; Cavallaro, R; Bosia, M; Lorenzi, C; Pirovano, A; Smeraldi, E; Benedetti, F. Catechol-O-methyltransferase (COMT) genotype biases neural correlates of empathy and perceived personal distress in schizophrenia. Compr. Psychiatry: 2013; 54(2): 181-186 - Article
Sarno, L; Di Mattei, V; Ratti, MM; Franchini, E; Ferrara, S; Rossi, A; Finocchiaro, CY; Grimoldi, M.
The rule of health psychology Services and their diffusion in Lombardia’s hospitals: main activities
and intervention setting. 27th Conference of the European Health Psychology Society, Bordeaux,
France, 16-20 July 2013, Proceedings
Sarno, L; Ratti, MM; Delli Zotti, GB; Rossi, A; Franchini, E; Ferrara, S; Spotti, D. Quality of life and
psychological issues of hemodialyzed patients. 27th Conference of the European Health Psychology
Society, Bordeaux, France, 16-20 July 2013, Proceedings
Vita, A; De Peri, L; Siracusano, A; Sacchetti, E; for the ATOM group. Efficacy and tolerability of asenapine for acute mania in bipolar I disorder: meta-analyses of randomized-controlled trials. Int Clin
Psychopharmacol: 2013; 28(5): 219-227 - Review
Zanardi, R; Colombo, L; Marcheggiani, E; Rossini, D; Delmonte, D; Cigala Fulgosi, M; Gavinelli, C; Colombo, C. Paroxetine drops versus paroxetine tablets: Evaluation of compliance in a sixmonth study. Riv. Psichiatr.: 2013; 48(3): 261-267 - Article
DEPARTMENT
OF
NEUROLOGY
Head of Department:
Giancarlo Comi*
CLINICAL UNIT LEADERS: Mauro Comola, Ubaldo Del Carro, Vittorio Martinelli, Fabio Minicucci
DISEASE UNIT COORDINATORS: Bruno Colombo, Raffaella Fazio, Letizia Leocani, Giuseppe
Magnani, Paolo Marchettini, Vittorio Martinelli, Lucia Moiola, Mariaemma Rodegher, Maria Sessa,
Giulio Truci, Maria Antonietta Volonté
PHYSICIANS: Stefano Amadio, Marco Bacigaluppi, Federica Cerri**, Raffaella Chieffo**, Maria Grazia
Deriu**, Federica Esposito**, Giovanna Franca Fanelli, Francesca Fumagalli**, Roberta Guerriero**,
Silvia Mammi, Filippo Martinelli-Boneschi, Stefania Medaglini, Maria Grazia Natali Sora, Grazia
Maria Nuzzaco**, Antonella Poggi, Marta Radaelli, Nilo Riva, Luisa Roveri, Marina Scarlato,
Francesca Spagnolo**
RESIDENTS: Martina Absinta**, Valeria Barcella**, Damiano Baroncini**, Francesca Bianchi**,
Francesca Caso**, Elisabetta Coppi**, Gloria Dalla Costa**, Dacia Dalla Libera**, Donatella De
Feo**, Giovanni Di Maggio**, Laura Ferrari**, Laura Ferrè**, Mario Fichera**, Sebastiano
Galantucci**, Giacomo Giacalone**, Clara Guaschino**, Matteo Impellizzeri**, Sara La Gioia**,
Emanuela Leopizzi**, Giuseppe Liberatore**, Giulia Longoni**, Ignazio Diego Lopez**, Arianna
Merlini**, Maria Josè Messina**, Roberta Messina**, Arturo Nuara**, Giulia Pavan**, Luca Peruzzotti
Jametti**, Paolo Preziosa**, Marzia Romeo**, Francesca Sangalli**, Roberto Santangelo**, Lidia
Sarro**, Edoardo Gioele Spinelli**, Laura Straffi**, Davide Strambo**, Daniele Velardo**
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
The Department of Neurology consists of the Neurology Unit (45 beds), the Neurorehabilitation Unit (42
beds), the laboratory of Clinical Neurophysiology and the Neuropsychology Service. The out patient area,
day hospital service and the Centres for Epilepsy, Multiple Sclerosis, Headache, Pain, ALS and Multiple
Sclerosis are the other activity characterising the Department. Clinical activities are organized in disease
units in order to provide patients an integrated assistance going from the diagnostic aspects to the advanced therapeutic interventions, including rehabilitation. The Department of Neurology is mostly qualified for advanced treatment strategies in inflammatory diseases of the Central and Peripheral Nervous
System, stroke, neurodegenerative disorders and is the clinical arm of the Institute of Experimental Neurology. A large number of phase I-IV clinical trials performed in cooperation with pharmaceutical industries and generated by the Department itself make it possible to provide patients with more advanced
therapeutic strategies. Points of excellence of the clinical research are etiologic and symptomatic treatment of multiple sclerosis, epidemiological studies on multiple sclerosis, and the evaluation of the disease
pathogenesis and pathophysiology. Ischemic stroke researches are focused on the risk factors for the
occurrence in young adults and on the organisational aspect of the early intervention. Studies on de
mentia are conducted in co-operation with Imaging and clinical Neurophysiology laboratories and aims
299
THE CLINICAL DEPARTMENTS
to define biomarkers specific for dementia subtypes and to assess the risk for evolution to Alzheimer Disease in patients with minimal cognitive impairment. In Amyotrophic Lateral Sclerosis the contribution of
instrumental test to the early diagnosis, the characterisation of cognitive dysfunction, the assessment of
the value of new treatments are the key research activities.
The recovery medicine is one of the more recent area of research activated in the Department, because
of the possibility to follow neurological dysfunctions due to acute central nervous system lesions, from the
onset to the recovery phase. The impact of various therapeutic strategies to enhance recovery, the functional and molecular bases underlying brain plasticity after acute damage with imaging and neurophysiological examinations are deeply investigated.
Giancarlo Comi
Selected publications
Agosta, F; Sala, S; Valsasina, P; Meani, A; Canu, E; Magnani, G; Cappa, SF; Scola, E; Quatto,
P; Horsfield, MA; Falini, A; Comi, G; Filippi, M. Brain network connectivity assessed using graph theory in frontotemporal dementia. Neurology: 2013; 81(2): 134-143 - Article
Cambiaghi, M and Cursi, M and Magri, L; Castoldi, V; Comi, G; Minicucci, F; Galli, R; Leocani,
L. Behavioural and EEG effects of chronic rapamycin treatment in a mouse model of Tuberous Sclerosis Complex. Neuropharmacology: 2013; 67: 1-7 - Article
Canu, E and Agosta, F; Spinelli, EG; Magnani, G; Marcone, A; Scola, E; Falautano, M; Comi,
G; Falini, A; Filippi, M. White matter microstructural damage in Alzheimer’s disease at different ages
of onset. Neurobiol. Aging: 2013; 34(10): 2331-2340 - Article
Caso, F; Onofrio, F; Falautano, M; Todeschini, P; Migliaccio, R; Comi, G; Perani, D; Magnani,
G. From primary progressive aphasia to corticobasal syndrome: two clinical and rCBF functional reports. Neurocase: 2013; 19(2): 201-207 - Article
Comi, G. Disease-modifying treatments for progressive multiple sclerosis. Mult. Scler.: 2013; 19(11):
1428-1436 - Review
Comi, G; Martinelli, V; Rodegher, M; Moiola, L; Leocani, L; Bajenaru, O; Carra, A; Elovaara, I;
Fazekas, F; Hartung, HP; Hillert, J; King, J; Komoly, S; Lubetzki, C; Montalban, X; Myhr, KM; Preziosa,
P; Ravnborg, M; Rieckmann, P; Rocca, MA; Wynn, D; Young, C; Filippi, M. Effects of early treatment with glatiramer acetate in patients with clinically isolated syndrome. Mult. Scler.: 2013; 19(8):
1074-1078 - Article
Dalla Costa, G; Colombo, B; Dalla Libera, D; Martinelli, V; Comi, G. Parry Romberg Syndrome
associated with chronic facial pain. J. Clin. Neurosci.: 2013; 20(9): 1320-1322 - Article
Filippi, M; Agosta, F; Scola, E; Canu, E; Magnani, G; Marcone, A; Valsasina, P; Caso, F; Copetti,
M; Comi, G; Cappa, SF; Falini, A. Functional network connectivity in the behavioral variant of frontotemporal dementia. Cortex: 2013; 49(9): 2389-2401 - Article
Martinelli-Boneschi, F; Giacalone, G; Magnani, G; Biella, G; Coppi, E; Santangelo, R; Brambilla,
P; Esposito, F; Lupoli, S; Clerici, F; Benussi, L; Ghidoni, R; Galimberti, D; Squitti, R; Confaloni, A;
Bruno, G; Pichler, S; Mayhaus, M; Riemenschneider, M; Mariani, C; Comi, G; Scarpini, E; Binetti, G;
Forloni, G; Franceschi, M; Albani, D. Pharmacogenomics in Alzheimer’s disease: A genome-wide association study of response to cholinesterase inhibitors. Neurobiol. Aging: 2013; 34(6): 1711.e71711.e13 - Article
Spagnolo, F; Coppi, E; Chieffo, R; Straffi, L; Fichera, M; Nuara, A; Gonzalez-Rosa, J; Martinelli,
V; Comi, G; Volonté, MA; Leocani, L. Interhemispheric balance in Parkinson’s disease: A transcranial magnetic stimulation study. Brain Stimul.: 2013; 6(6): 892-897 - Article
DEPARTMENT
ONCO-HAEMATOLOGYOF
Head of Department:
Federico Caligaris-Cappio*
DEPARTMENT AREA COORDINATORS: Gianfranco Ciboddo, Consuelo Corti
Internal medicine
HEAD OF UNIT: Federico Caligaris-Cappio*
CLINICAL UNIT LEADER: Marco Foppoli
CLINICAL UNIT COORDINATORS: Andrés José Marìa Ferreri, Paolo Ghia*
PHYSICIANS: Marta Bruno Ventre (until June 2013), Gianfranco Ciboddo, Giovanni Citterio, Giovanni
Donadoni, Silvia Govi (until September 2013), Marianna Sassone (since September 2013)
RESIDENTS: Serena Antoniolli, Elena Brioschi, Gaetano Di Terlizzi, Chiara Giudice, Chiara Miggiano,
Sara M. Rosa Previtali, Carlo Rossi, Lydia Scarfò, Paolo Strati, Gabriele Todisco, Alessandro Vignati
Haematology and bone marrow transplantation
HEAD OF UNIT: Fabio Ciceri
CLINICAL GROUP LEADER: Massimo Bernardi
PHYSICIANS: Andrea Assanelli, Matteo Carrabba, Consuelo Corti, Fabio Giglio, Elena Guggiari,
Francesca Lunghi, Maria Teresa Lupo Stanghellini, Magda Marcatti, Sarah Marktel, Sara Mastaglio,
Mara Morelli, Jacopo Peccatori
RESIDENTS: Simone Claudiani**, Alessandra Forcina**, Barbara Forno**, Bernhard Gentner**,
Stefania Girlanda**, Raffaella Greco**, Francesca Lorentino**, Carlo Messina**, Francesca
Pavesi**, Simona Piemontese**, Elisa Sala**, Luca Vago**
STUDY COORDINATOR: Stefania Trinca
RESEARCH NURSE: Margherita Brambilla
DATA MANAGER: Ambra Malerba
TECHNICIAN: Fernanda Tripiciano
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
The aim of the Department is to achieve optimization of care and acceleration of cure of blood cancers by implementing the transformation of everyday practice into protocol-based and clinical-trial-based
clinical activity. To this end we are strengthening the clinical application of Translational Research by establishing interactions with other Departments involved in the diagnosis and treatment of cancer (especially the Departments of Oncology and Pathology) and joining efforts with several Research Divisions
301
THE CLINICAL DEPARTMENTS
especially the Division of Molecular Oncology. Specific goals are: 1) to maintain/reach “state of the art”
clinical care for all types of blood cancers; 2) to improve logistic and organization for ameliorating patient
care; 3) to become second to none in specific cancers such as lymphoid malignancies.
Clinical activity and Areas of excellence
The Department includes the quality-certified Divisions of Medicine 1QB and of Hematology and Bone
Marrow Transplantation (BMT) with ample out-patient (and Day Hospital) activity, research nurses and
data managers. Fruitful interactions with other Departments and with Research Divisions allow to bridge
the clinical experience in applying new therapies in close contact with the development of new potential
therapeutic tools systematically analysed in preclinical settings. Furthermore a) the Department is full
member of the ROL (Oncology Network of Lombardia Region) and the REL (Hematology Network of
Lombardia Region), b) the Departmental Area of Lymphoid Tumors has been blooming with more than
200 new patients/year and more than 40 ongoing clinical trials, c) the BMT Unit has ranked among the
firsts in Italy as for the number of allogeneic transplantations performed and d) new clinical trials, including Phase I, Phase II and Phase III trials with innovative molecules, usually in the context of international
collaborations, are constantly approved by the Ethical Committee.
The Department is member of the European Organization of Cancer Centers (OECI), the Southern Europe for New Drugs Organization (SENDO), the Cancer Research UK (CRUK), the Swiss Group for Clinical Cancer Research (SAKK), the EBMT (European Bone Marrow Transplantation), the International
Extranodal Lymphoma Study Group (IELSG), the International PCNSL Collaborative Group (IPCG), the European PCNSL Collaborative Group (EPCG), the Lymphoma Study Association (LYSA), the Nordic Lymphoma Group (NLG), the European Splenic Lymphoma Group (ESLG), the European Gastrointestinal
Lymphomas Study Group (EGILS), the ERIC (European Research Initiative on CLL) and the CLL US/Europe Alliance Organization (driven by the MD Anderson Cancer Center).
Fields of research
We keep on building teams of laboratory-based and clinical investigators to define molecular endpoints
in clinical material, develop studies on the pato-biology of specific tumours and organize pilot studies and
investigator-driven clinical trials. The currently ongoing projects can be summarized under two main headings: 1) Molecular mechanisms of disease and their clinical translation in terms of prognostic/predictive
factors with the definition of new biologically-based tools; 2) Novel treatment strategies developed by a)
increasing the number and quality of clinical studies and b) clinically translating the results of preclinical
investigations, examples being immunotherapy and BMT, anti-angiogenesis-based treatments and the use
of several new investigational drugs.
Federico Caligaris-Cappio
Selected publications
Apollonio, B; Scielzo, C; Bertilaccio, MT; Ten Hacken, E; Scarfò, L; Ranghetti, P; Stevenson,
F; Packham, G; Ghia, P; Muzio, M and Caligaris-Cappio, F. Targeting B-cell anergy in chronic
lymphocytic leukemia. Blood: 2013; 121(19): 3879-3888 - Article
Bertilaccio, MTS; Scielzo, C; Simonetti, G; Ten Hacken, E; Apollonio, B; Ghia, P; CaligarisCappio, F. Xenograft models of chronic lymphocytic leukemia: Problems, pitfalls and future directions. Leukemia: 2013; 27(3): 534-540 - Review
Ciceri, F; Lupo-Stanghellini, MT; Korthof, ET; on behalf of the SAA-WP EBMT. Haploidentical
transplantation in patients with acquired aplastic anemia. Bone Marrow Transplant.: 2013; 48(2):
183-185 - Review
Cieri, N; Camisa, B; Cocchiarella, F; Forcato, M; Oliveira, G; Provasi, E; Bondanza, A; Bordignon, C; Peccatori, J; Ciceri, F; Lupo-Stanghellini, MT; Mavilio, F; Mondino, A; Bicciato, S;
Recchia, A; Bonini, C. IL-7 and IL-15 instruct the generation of human memory stem T cells from
naive precursors. Blood: 2013; 121(4): 573-584 - Article
Fonte, E; Apollonio, B; Scarfò, L; Ranghetti, P; Fazi, C; Ghia, P; Caligaris-Cappio, F; Muzio,
THE CLINICAL DEPARTMENTS
M. In vitro sensitivity of CLL cells to fludarabine may be modulated by the stimulation of toll-like receptors. Clin. Cancer Res.: 2013; 19(2): 367-379 - Article
Ghielmini, M; Vitolo, U; Kimby, E; Montoto, S; Walewski, J; Pfreundschuh, M; Federico, M; Hoskin,
P; McNamara, C; Caligaris-Cappio, F; Stilgenbauer, S; Marcus, R; Trneny, M; Dreger, P; Montserrat, E; Dreyling, M; on behalf of the Panel Members of the 1st ESMO Consensus Conference on
Malignant Lymphoma. ESMO guidelines consensus conference on malignant lymphoma 2011 part
1: Diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL) and Chronic Lymphocytic
Leukemia (CLL). Ann. Oncol.: 2013; 24(3): 561-576 - Article
Lo-Coco, F; Avvisati, G; Vignetti, M; Thiede, C; Orlando, SM; Iacobelli, S; Ferrara, F; Fazi, P; Cicconi, L; Di Bona, E; Specchia, G; Sica, S; Divona, M; Levis, A; Fiedler, W; Cerqui, E; Breccia, M; Fioritoni, G; Salih, HR; Cazzola, M; Melillo, L; Carella, AM; Brandts, CH; Morra, E; Von Lilienfeld-Toal, M;
Hertenstein, B; Wattad, M; Lubbert, M; Hanel, M; Schmitz, N; Link, H; Kropp, MG; Rambaldi, A; La
Nasa, G; Luppi, M; Ciceri, F; Finizio, O; Venditti, A; Fabbiano, F; Dohner, K; Sauer, M; Ganser, A;
Amadori, S; Mandelli, F; Dohner, H; Ehninger, G; Schlenk, RF; Platzbecker, U; for Gruppo Italiano
Malattie Ematologiche dell’Adulto; the German-Austrian Acute Myeloid Leukemia Study Group; and
Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. New
Engl. J. Med.: 2013; 369(2): 111-121 - Article
Maffi, P and Balzano, G; Ponzoni, M; Nano, R; Sordi, V; Melzi, R; Mercalli, A; Scavini, M;
Esposito, A; Peccatori, J; Cantarelli, E; Messina, C; Bernardi, M; Del Maschio, A; Staudacher,
C; Doglioni, C; Ciceri, F; Secchi, A; Piemonti, L. Autologous Pancreatic Islet Transplantation in
Human Bone Marrow. Diabetes: 2013; 62(10): 3523-3531 - Article
ten Hacken, E and Scielzo, C; Bertilaccio, MT; Scarfò, L; Apollonio, B; Barbaglio, F; Stamatopoulos, K; Ponzoni, M; Ghia, P; Caligaris-Cappio, F. Targeting the LYN/HS1 signaling axis in
chronic lymphocytic leukemia. Blood: 2013; 121(12): 2264-2273 - Article
Todisco, E; Ciceri, F; Oldani, E; Boschini, C; Mico, C; Vanlint, MT; Donnini, I; Patriarca, F; Alessandrino, PE; Bonifazi, F; Arcese, W; Barberi, W; Marenco, P; Terruzzi, E; Cortelazzo, S; Santarone, S;
Proia, A; Corradini, P; Tagliaferri, E; Falcioni, S; Irrera, G; Dallanegra, L; Castagna, L; Santoro, A;
Camboni, A; Sacchi, N; Bosi, A; Bacigalupo, A; Rambaldi, A. The CIBMTR score predicts survival of
AML patients undergoing allogeneic transplantation with active disease after a myeloablative or reduced intensity conditioning: A retrospective analysis of the Gruppo Italiano Trapianto di Midollo Osseo. Leukemia: 2013; 27(10): 2086-2091 - Letter
303
DEPARTMENT
MEDICAL ONCOLOGY OF
Head of Department:
Luca Gianni
DEPARTMENT AREA COORDINATORS: Gianni Bordogna, Vanesa Gregorc, Michele Reni, Cristiana
Sessa, Milvia Zambetti
Medical oncology
HEAD OF UNIT: Luca Gianni
CLINICAL UNIT LEADERS: Daniela Aldrighetti, Vanesa Gregorc, Giovanna Petrella, Monica Ronzoni,
Cristiana Sessa, Aurelio Vicari, Milvia Zambetti
PHYSICIANS: Gianni Bordogna, Stefano Cereda, Gianluca Del Conte, Angelica Fasolo, Elena Mazza,
Manuela Pacchioni, Antonella Perotti, Michele Reni, Giordano Pietro Vitali, Patrizia Zucchinelli
PHYSICIAN SCIENTIST: Giampaolo Bianchini
CONSULTANTS: Carmen Belli, Alessandra Bulotta, Francesca Colonese, Vincenzo Ricci, Alessia
Rognone, Gilda Rossoni, Maria Grazia Viganò, Stefania Zambelli
The Department of Medical Oncology has the goals of 1) providing clinical care based on “state of the
art” treatment for all types of solid tumors through the activity of interdisciplinary Disease Units dedicated
to the coordinated diagnosis and therapy of specific neoplasms; 2) fostering high level basic, translational
and clinical research; 3) educating teaching and tutoring students, nurses, fellows, and residents with active participation to the activity of Università Vita-salute San Raffaele. The Department has continued and
increased all its activities in 2013 within the Ospedale San Raffaele and the Scientific Institute.
Clinical activity and Areas of excellence
The Department has two in-patient units including one for emergencies in oncologic patients for total 27
beds; outpatient activities in an Ambulatory Service of 14 visit rooms; and a Day Hospital for delivery of
anticancer therapies. The personnel counts 50 people including clinical trials assistants and research
nurses. Clinical activity is conducted through interdisciplinary Disease Units. Currently Disease Units are
operational for patients with tumors of the breast, lung, pancreas, biliary tract, gastrointestinal, liver, central nervous system, genito-urinary, head and neck, and melanoma. In each Unit a group of Physicians
is dedicated to the treatment and follow up of patients according to guidelines or to approved experimental protocols. There also is a Phase I Unit. The collaboration with the Division of Molecular Oncology
is strengthened by the clinical experience in applying new therapies to patients and is favoring the development of new potential therapeutic tools that are systematically analysed in preclinical settings. In
2013 the Department has taken care of more than 3000 cases in inpatient and outpatient services. The
Department is full member of the ROL (Oncology Network of Lombardia Region); has had 11 new clinical trials approved by the Ethical Committee, and has been conducting overall 53 trials. Four newly approved protocols are investigators initiative trials. Overall 21investigators initiative trials are ongoing in the
THE CLINICAL DEPARTMENTS
Department. Over 60 lesson hours have been taught to students of the faculty of Medicine and of Dental Hygiene, to nurses and fellows. Overall 35 scientific manuscripts were published.
The Department is member of the Michelangelo Foundation for cooperative studies in breast cancer, the
European Organization Research and Treatment of Cancer Brain Tumor Group (EORTC), the pancreas
Aide et Recherche en CAncérologie Digestive (ARCAD) group, the Associazione Italiana Studi Pancreas
(AISP), the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO), and the Italian Melanoma Intergroup.
Fields of research
The Department is committed to conduct clinical trials in collaboration with the pharmaceutical industry,
and to design and conduct investigator-driven clinical trials. Special emphasis is given to new drugs development and collaborations with laboratory researchers to identify molecular prognostic or predictive biomarkers. Ongoing projects can be listed under three headings: 1) Molecular mechanisms of disease
driven phase I trials; 2) Definition of molecular prognostic/predictive tools on markers generated by assays of gene expression, proteomics and single nucleotide polymorphisms involved; 3) New treatment
strategies developed by phase I/II studies and by translation of the results of preclinical investigations. In
all these fields the Department has reached relevant results in 2013. Phase I trials were opened with PI3K
inhibitors in different combinations according to the type of neoplastic disease to be treated (platinating
agents, aromatase inhibitors, MEK inhibitors). Based on analyses of gene expression profiles conducted
within the Department, it has been shown that the immune system plays a key role in women with breast
cancer in determining the probability of tumor eradication with drug treatment. In particular this analysis
has led to the design of a study that will use the immune check point directed monoclonal antibody antiPDL1 in comination with HER2-directed monoclonals in HER2 positive breast cancer in an attempt to improve efficacy without use of chemotherapy. Another similar study has been designed and approved for
women with triple negative breast cancer. Also notable is the continuous contribution of the Department
to the development of new therapies in patients with pancreatic carcinoma and lung cancers. The role
of combination chemotherapy in stage IV disease; of maintenance therapy in stage IV disease; and of predictive role of single nucleotide polymorphisms in advanced disease were explored in pancreatic cancer.
In lung cancer the use of proteomic analysis to select patients who will or will not benefit of specific therapies has seen the completion of an investigator-initiative study with promising results on the utility of approach.
Luca Gianni
Selected publications
Bianchini, G; Pusztai, L; Karn, T; Iwamoto, T; Rody, A; Kelly, CM; Müller, V; Schmidt, M; Qi, Y; Holtrich, U; Becker, S; Santarpia, L; Fasolo, A; Del Conte, G; Zambetti, M; Sotiriou, C; Haibe-Kains,
B; Symmans, WF; Gianni, L. Proliferation and estrogen signaling can distinguish patients at risk for
early versus late relapse among estrogen receptor positive breast cancers. Breast Cancer Res.:
2013; 15: R86 - Article
Belli, C; Cereda, S; Anand, S; Reni, M. Neoadjuvant therapy in resectable pancreatic cancer: A
critical review. Cancer Treat. Rev.: 2013; 39(5): 518-524 - Review
Corti, A; Curnis, F; Rossoni, G; Marcucci, F; Gregorc, V. Peptide-mediated targeting of cytokines
to tumor vasculature: the NGR-hTNF example. BioDrugs: 2013; 27(6): 591-603 - Review
Fasolo, A; Sessa, C; Gianni, L; Broggini, M. Seminars in clinical pharmacology: An introduction to
met inhibitors for the medical oncologist. Ann. Oncol.: 2013; 24(1): 14-20 - Review
Gianni, L; Romieu, GH; Lichinitser, M; Serrano, SV; Mansutti, M; Pivot, X; Mariani, P; Andre, F;
Chan, A; Lipatov, O; Chan, S; Wardley, A; Greil, R; Moore, N; Prot, S; Pallaud, C; Semiglazov, V.
AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and
trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J. Clin.
Oncol.: 2013; 31(14): 1719-1725 - Article
Goldhirsch, A; Gelber, RD; Piccart-Gebhart, MJ; De Azambuja, E; Procter, M; Suter, TM; Jackisch,
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THE CLINICAL DEPARTMENTS
C; Cameron, D; Weber, HA; Heinzmann, D; Lago, LD; McFadden, E; Dowsett, M; Untch, M; Gianni, L; Bell, R; Kohne, CH; Vindevoghel, A; Andersson, M; Brunt, AM; Otero-Reyes, D; Song, S;
Smith, I; Leyland-Jones, B; Baselga, J. 2 years versus 1 year of adjuvant trastuzumab for HER2positive breast cancer (HERA): An open-label, randomised controlled trial. Lancet: 2013; 382(9897):
1021-1028 - Article
Passoni, P; Fiorino, C; Slim, N; Ronzoni, M; Ricci, V; Di Palo, S; De Nardi, P; Orsenigo, E;
Tamburini, A; De Cobelli, F; Losio, C; Iacovelli, NA; Broggi, S; Staudacher, C; Calandrino, R;
Di Muzio, N. Feasibility of an adaptive strategy in preoperative radiochemotherapy for rectal cancer
with image-guided tomotherapy: Boosting the dose to the shrinking tumor. Int. J. Radiat. Oncol. Biol.
Phys.: 2013; 87(1): 67-72 - Article
Pecorelli, N; Braga, M; Doglioni, C; Balzano, G; Reni, M; Cereda, S; Albarello, L; Castoldi, R;
Capretti, G; Di Carlo, V. Preoperative Chemotherapy Does Not Adversely Affect Pancreatic Structure and Short-Term Outcome after Pancreatectomy. J. Gastrointest. Surg.: 2013; 17(3): 488-493 Article
Sessa, C; Del Conte, G; Christinat, A; Cresta, S; Perotti, A; Gallerani, E; Lardelli, P; Kahatt, C; Alfaro, V; Iglesias, JL; Fernandez-Teruel, C; Gianni, L. Phase I clinical and pharmacokinetic study of
trabectedin and cisplatin given every three weeks in patients with advanced solid tumors. Invest.
New Drugs: 2013; 31(5): 1236-1243 - Article
Tartarone, A; Lazzari, C; Lerose, R; Conteduca, V; Improta, G; Zupa, A; Bulotta, A; Aieta, M; Gregorc, V. Mechanisms of resistance to EGFR tyrosine kinase inhibitors gefitinib/erlotinib and to ALK
inhibitor crizotinib. Lung Cancer: 2013; 81(3): 328-336 - Review
DEPARTMENT
OF
RADIOLOGY
Head of Department:
Alessandro Del Maschio*
DEPARTMENT AREA COORDINATORS: Francesco De Cobelli*, Maurizia Del Maschio, Roberto
Nicoletti, Pierluigi Paesano
Radiology OSR
HEAD OF UNIT: Alessandro Del Maschio*
CLINICAL UNIT LEADERS: Francesco De Cobelli*, Maurizia Del Maschio, Roberto Nicoletti, Pierluigi
Paesano, Maria Grazia Rodighiero, Massimo Venturini
PHYSICIANS: Laura Brasca, Stefano Cappio, Giulia Maria Crespi, Angela De Gaspari, Antonio
Esposito*, Elda Garuti, Domenico Ghio, Simone Gusmini, Claudio Losio, Carlo Martinenghi, Renata
Mellone, Marco Salvioni, Simona Irma Tacchini, Roberto Varagona
CONSULTANTS: Elena Contrino, Silvia Ravelli, Elena Schiani
Radiology OSRT
HEAD OF UNIT: Giuseppe Balconi
CLINICAL UNIT LEADER: Gianpiero Cardone
PHYSICIANS: Elena Capitelli, Roberto Lanzi, Massimo Mandelli, Maurizio Papa
CONSULTANT: Rossana Favia
RESIDENT: Audrey Serafini
TECHNICIANS: Cecilia Bertocchi, Enza Galvano, Caterina Parolo, Alessandra Poggi, Maria Pia
Rapallo, Stefano Rovani
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
The activity of the Department of Radiology is based upon both inpatient and outpatients Services
covering all the main fields of general Radiology. The Department of Radiology works in tight interaction
with the most important research groups of the Hospital allowing to reach very important results in terms
of number and quality of research lines.
The objective of the Department is to integrate clinical activity, research and education with the aim of
helping patients at the best of current medical knowledge and technological expertise.
Clinical activity and Areas of excellence
The Department includes six sections of clinical activity and areas of excellence:
1. Conventional and Digital Radiology
2. Breast Imaging
3. Ultrasound
307
THE CLINICAL DEPARTMENTS
4. Computed Tomography
5. Magnetic Resonance Imaging
6. Diagnostic and Interventional Radiology/Angiography
Fields of research
1. Interventional Radiology.
• Transarterial chemoembolization (TACE) with Drug-Eluting-Beads preloaded with Irinotecan (DEBIRI)in
the treatment of unresectable hepatic metastases confined to the liver from uveal melanoma (first line
treatment), cholangiocarcinoma (second line treatment), colorectal cancer (third line treatment).
• First phase-1 study in the treatment of Duchenne Muscular Dystrophy (DMD) by multiple intra-arterial transplantations of mesoangioblasts in dystrophic children.
• Percutaneous intraportal islet auto-transplantation to prevent diabetes after extensive pancreatic surgery.
• Endovascular treatment of visceral artery aneurysms by trans arterial embolization, covered stents and
combined technique (embolization associated with covered/uncovered stent).
• Drug-eluting-stent in peripheral occlusive disease due to Takayasu arteritis.
2. Ultrasound
• Contrast-enhanced ultrasound (CEUS) in the quantitative assessment of uveal melanoma (UM) response to gamma knife radiosurgery (GKR).
• Orbital Color Doppler Ultrasound application in dural fistulas, ischemic optic neuropathy, type 1 diabetes, and as monitoring during cardiac surgery.
3. Imaging of islet transplantation
MRI based functional assessment of micro-vascular events occurring after pancreatic islets transplantation and relationship with graft outcome.
4. Cardiac Imaging
The main cardiac study projects were focused on:
• Myocarditis: in order to find prognostic imaging markers for patients at risk of ventricular tachyarrhythmias and sudden death.
• Cardiac CT and Cardiac MRI assessment of structural substrate of ventricular tachycardia; 3D imaging based modeling of the heart/coronary anatomy and scars localization as a tool to be merged
with electro-anatomic maps for a real time anatomical/structural/electrical guide of ventricular tachycardia ablation.
• A cardiac MR-study to evaluate the effect of GH-deficiency in patients’ heart.
• Characterization of cardiac masses.
• Optimization of Cardiac-CT protocols for the assessment coronary arteries in re-vascularized patients.
• Patients with AMI submitted to PCI in order to evaluate the microvascular obstruction and to compare our results with coronary angiographyand to find new prognostic factors.
5. Oncologic MR Imaging
We aimed to evaluate the accuracy of Diffusion-weighted Imaging (DWI) as a marker of tumour aggressiveness and tumour response to chemotherapy. We demonstrated the correlation between ADC and tumour grading factors in prostate, gastroesophageal and rectal cancer and that changes in ADC before
and after neoadjuvant-treatment can be used as reliable marker of tumor response. Moreover, we implemented the use of imaging in radiotherapy planning, in particular MR and DWI-MR to improve target
volume definition in pancreas and rectal tumors.
6. Breast Imaging
• Two large multicenter studies are ongoing investigating the role of Breast-MRI in two different settings:
• a. as an alternative tool to mammography and ultrasound in the screening of women at intermediate risk of breast cancer (MRIB study)
• b. to demonstrate the outperformance of MRI over traditional imaging in the pre-surgical planning of
patients diagnosed with breast cancer (MIPA study)
THE CLINICAL DEPARTMENTS
• Assessment of tumor response in women with locally-advanced breast cancer undergoing neoadjuvant chemotherapy:
• a. by multimodality imaging: trying to identify the best technique to monitor tumor shrinkage and
residual disease according to morphologic features of different tumor types
• b. by means of MRI: investigating all parameters that could predict subsequent response or resistance to chemotherapy, including Diffusion-Weighted Imaging
• c. Characterization of breast architectural distortions by means of MRI.
Alessandro Del Maschio
Selected publications
Balzano, G; Maffi, P; Nano, R; Zerbi, A; Venturini, M; Melzi, R; Mercalli, A; Magistretti, P; Scavini, M; Castoldi, R; Carvello, M; Braga, M; Del Maschio, A; Secchi, A; Staudacher, C; Piemonti, L. Extending indications for islet autotransplantation in pancreatic surgery. Ann. Surg.: 2013;
258(2): 210-218 - Article
De Cobelli, F; Giganti, F; Orsenigo, E; Cellina, M; Esposito, A; Agostini, G; Albarello, L; Mazza,
E; Ambrosi, A; Socci, C; Staudacher, C; Del Maschio, A. Apparent diffusion coefficient modifications in assessing gastro-oesophageal cancer response to neoadjuvant treatment: comparison with
tumour regression grade at histology. Eur. Radiol.: 2013; 23(8): 2165-2174 - Article
Esposito, A and Campana, L; Palmisano, A; De Cobelli, F; Canu, T; Santarella, F; Colantoni,
C; Monno, A; Vezzoli, M; Pezzetti, G; Manfredi, AA; Rovere-Querini, P; Del Maschio, A. Magnetic Resonance Imaging at 7T Reveals Common Events in Age-Related Sarcopenia and in the
Homeostatic Response to Muscle Sterile Injury. PLoS ONE: 2013; 8(3): e59308 - Article
Esposito, A; Colantoni, C; De Cobelli, F; Del Vecchio, A; Palmisano, A; Calandrino, R; Del
Maschio, A. Multidetector computed tomography for coronary stents imaging: High-voltage (140KVP) prospective ecg-triggered versus standard-voltage (120-kvp) retrospective ecg-gated helical
scanning. J. Comput. Assisted Tomogr.: 2013; 37(3): 395-401 - Article
Losa, A; Gadda, GM; Lazzeri, M; Lughezzani, G; Cardone, G; Freschi, M; Lista, G; Larcher, A;
Nava, LD; Guazzoni, G. Complications and quality of life after template-assisted transperineal
prostate biopsy in patients eligible for focal therapy. Urology: 2013; 81(6): 1291-1296 - Article
Maffi, P and Balzano, G; Ponzoni, M; Nano, R; Sordi, V; Melzi, R; Mercalli, A; Scavini, M;
Esposito, A; Peccatori, J; Cantarelli, E; Messina, C; Bernardi, M; Del Maschio, A; Staudacher,
C; Doglioni, C; Ciceri, F; Secchi, A; Piemonti, L. Autologous Pancreatic Islet Transplantation in
Human Bone Marrow. Diabetes: 2013; 62(10): 3523-3531 - Article
Passoni, P; Fiorino, C; Slim, N; Ronzoni, M; Ricci, V; Di Palo, S; De Nardi, P; Orsenigo, E;
Tamburini, A; De Cobelli, F; Losio, C; Iacovelli, NA; Broggi, S; Staudacher, C; Calandrino, R;
Di Muzio, N. Feasibility of an adaptive strategy in preoperative radiochemotherapy for rectal cancer
with image-guided tomotherapy: Boosting the dose to the shrinking tumor. Int. J. Radiat. Oncol. Biol.
Phys.: 2013; 87(1): 67-72 - Article
Piatti, PM; Marone, E; Mantero, M; Setola, E; Galluccio, E; Lucotti, P; Shehaj, E; Villa, V; Perticone, F; Venturini, M; Palini, A; Airoldi, F; Faglia, E; Del Maschio, A; Colombo, A; Chiesa, R; Bosi, E;
Monti, LD. Effect of normalization of fasting glucose by intensified insulin therapy and influence of
eNOS polymorphisms on the incidence of restenosis after peripheral angioplasty in patients with type 2
diabetes: a randomized, open-label clinical trial. Acta Diabetol.: 2013; 50(3): 373-382 - Article
Russo, V and Pilla, L; Lunghi, F; Crocchiolo, R; Greco, R; Ciceri, F; Maggioni, D; Fontana, R;
Mukenge, S; Rivoltini, L; Rigamonti, G; Mercuri, SR; Nicoletti, R; Del Maschio, A; Gianolli, L;
Fazio, F; Marchianò, A; Di Florio, A; Maio, M; Salomoni, M; Gallo-Stampino, C; Del Fiacco, M; Lambiase, A; Coulie, PG; Patuzzo, R; Parmiani, G; Traversari, C; Bordignon, C; Santinami, M and Bregni, M. Clinical and immunologic responses in melanoma patients vaccinated with MAGE-A3genetically modified lymphocytes. Int. J. Cancer: 2013; 132(11): 2557-2566 - Article
Venturini, E; Losio, C; Panizza, P; Rodighiero, MG; Fedele, I; Tacchini, S; Schiani, E; Ravelli, S;
Cristel, G; Panzeri, MM; De Cobelli, F; Del Maschio, A. Tailored breast cancer screening program with microdose mammography, us, and mr imaging : Short-term results of a pilot study in 4049-year-old wome. Radiology: 2013; 268(2): 347-355 - Article
309
DEPARTMENT
OF
UROLOGY
Francesco Montorsi*
Clinical Unit of Urology - San Raffaele Hospital
Giorgio Guazzoni*
Clinical Unit of Urology - San Raffaele Turro
Urology OSR
HEAD OF UNIT: Francesco Montorsi*
CLINICAL UNIT COORDINATORS: Roberto Bertini, Alberto Briganti, Renzo Colombo, Federico Dehò
(since October 2013), Andrea Salonia, Vincenzo Scattoni
PHYSICIANS: Lina Bua, Umberto Capitanio, Andrea Gallina, Massimo Ghezzi (until June 2013),
Caterina Lania, Arianna Lesma, Carmen Maccagnano (until April 2013), Ryan Matloob (since
August 2013), Nazareno Suardi (until April 2013), Giuseppe Zanni
RESIDENTS: Marco Bianchi**, Paolo Capogrosso**, Giulia Maria Castagna** (since August 2013),
Fabio Castiglione**, Stefano Corti**, Dario Di Trapani**, Ettore Di Trapani**, Matteo Ferrari** (until
March 2013), Giorgio Gandaglia**, Giovanni La Croce**, Ryan Matloob (until July 2013),
Alessandro Nini** (since August 2013), Lorenzo Rocchini**, Andrea Russo**, Manuela Tutolo**,
Luca Villa**
Urological endoscopy service and day surgery
HEAD OF UNIT: Valerio Di Girolamo
Strategic Program for uro-andrological research
HEAD OF UNIT: Francesco Montorsi*
THE CLINICAL DEPARTMENTS
Urology OSRT
HEAD OF UNIT: Giorgio Guazzoni*
CLINICAL UNIT LEADERS: Piera Bellinzoni, Luigi Broglia, Andrea Cestari (until June 2013)
PHYSICIANS: Nicolò Maria Buffi , Antonia Centemero, Andrea Losa, Tommaso Maga, Lorenzo Rigatti,
Giovanni Lughezzani
CONSULTANTS: Vincenzo Dell’Acqua, Girolamo Fiorini
RESIDENTS: Paolo Dell’Oglio**, Nicola Fossati **, Giulio Maria Gadda**, Ella Kinzikeeva **, Alessandro
Larcher**, Giuliana Lista**
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
The Department of Urology at Vita-Salute San Raffaele University, Milan, is composed of two clinical
and research units (Ospedale San Raffele Sede Centrale and San Raffaele Turro) chaired by Professor
Francesco Montorsi and Professor Giorgio Guazzoni, respectively.
The Department was founded in 1985 and it has been directed by Professor Patrizio Rigatti until November 2012.
Clinical activity
The surgical activity is based on 25 operating theatre sessions weekly and it is serving 80 beds for ordinary recovery. Every year, about 1000, 500 and 250 surgical procedures are performed for prostate,
bladder and kidney cancer, respectively.
There is a continue effort to set the highest standards of care for patients with urological conditions,
ground-breaking surgical techniques, professional education, teaching and training.
Specific interest is directed to robotic surgery which is currently used to perform radical prostatectomy,
partial nephrectomy for cancer, radical cystectomy and reconstructive. Likewise, the two units have been
involved in highly challenging surgical procedures (extra-corporeal circulation and deep hypothermic circulatory arrest for cavo-atrial neoplastic thrombosis of kidney or adrenal cancer).
In 2012, our department surpassed its objectives in terms of ward organization, clinical information organization and management, quality of clinical outcomes, and the level of patients’ satisfaction.
Fields of research
The clinical investigations performed in the most recent years leaded to the publication of 283 scientific
contributions throughout the last three years (2010-2012) for a overall citation index of 7752; h-index: 58
(citation index 2012: 439; h-index: 11) [Source SCOPUS June 2013]. During the last 4 years the Department of Urology ranked first in terms of abstracts presented at the official annual meetings of the European Association of Urology and American Urological Association.
The main clinical research areas consist of prostate cancer, kidney cancer, bladder cancer, infertility and
andrology, female sexual medicine, benign prostatic hyperplasia. Ongoing and new translational researches have been starting after the foundation of the Urological Research Institute (URI), headed by Professors Francesco Montorsi and Petter Hedlund. The main basic research areas consist of prostate and
bladder cancer, functional urology, reproductive and erectile dysfunction. In 2010, a biological bank was
founded to permit collecting and analyzing tissue, blood, and urine samples from virtually all oncological
patients for scientific research purpose.
Francesco Montorsi and Giorgio Guazzoni
311
THE CLINICAL DEPARTMENTS
Selected publications
Abdollah, F; Suardi, N; Cozzarini, C; Gallina, A; Capitanio, U; Bianchi, M; Sun, M; Fossati, N;
Passoni, NM; Fiorino, C; Di Muzio, N; Karakiewicz, PI; Rigatti, P; Montorsi, F; Briganti, A. Selecting the Optimal Candidate for Adjuvant Radiotherapy After Radical Prostatectomy for Prostate
Cancer: A Long-term Survival Analysis. Eur. Urol.: 2013; 63(6): 998-1008 - Article
Briganti, A; Bianchi, M; Sun, M; Suardi, N; Gallina, A; Abdollah, F; Bertini, R; Colombo, R; Di
Girolamo, V; Salonia, A; Scattoni, V; Karakiewicz, PI; Guazzoni, G; Rigatti, P; Montorsi, F. Impact of the introduction of a robotic training programme on prostate cancer stage migration at a single tertiary referral centre. BJU Int.: 2013; 111(8): 1222-1230 - Article
Buffi, N; Lista, G; Larcher, A; Lughezzani, G; Cestari, A; Lazzeri, M; Guazzoni, G; Ficarra, V.
Re: “Trifecta” in Partial Nephrectomy: A. J. Hung, J. Cai, M. N. Simmons and I. S. Gill J Urol 2013;
189: 36–42. J. Urol.: 2013; 190(2): 810-811 - Reply
Capitanio, U; Abdollah, F; Matloob, R; Suardi, N; Castiglione, F; Di Trapani, E; Capogrosso,
P; Gallina, A; Dell’Oglio, P; Briganti, A; Salonia, A; Montorsi, F; Bertini, R. When to perform
lymph node dissection in patients with renal cell carcinoma: a novel approach to the preoperative
assessment of risk of lymph node invasion at surgery and of lymph node progression during followup. BJU Int: 2013; 112(2): E59-E66 - Article
Capogrosso, P; Colicchia, M; Ventimiglia, E; Castagna, G; Clementi, MC; Suardi, N; Castiglione, F; Briganti, A; Cantiello, F; Damiano, R; Montorsi, F; Salonia, A. One patient out of four
with newly diagnosed erectile dysfunction is a young man—worrisome picture from the everyday
clinical practice. J. Sex. Med.: 2013; 10(7): 1833-1841 - Article
Castiglione, F; Hedlund, P; Van der Aa, F; Bivalacqua, TJ; Rigatti, P; Van Poppel, H; Montorsi, F;
De Ridder, D; Albersen, M. Intratunical Injection of Human Adipose Tissue-derived Stem Cells Prevents Fibrosis and Is Associated with Improved Erectile Function in a Rat Model of Peyronie’s Disease. Eur. Urol.: 2013; 63(3): 551-660 - Article
Lazzeri, M; Haese, A; Abrate, A; De La Taille, A; Redorta, JP; McNicholas, T; Lughezzani, G; Lista, G; Larcher, A; Bini, V; Cestari, A; Buffi, N; Graefen, M; Bosset, O; Corvoisier, PL; Breda, A;
De La Torre, P; Fowler, L; Roux, J; Guazzoni, G. Clinical performance of serum prostate-specific
antigen isoform [-2]proPSA (p2PSA) and its derivatives, %p2PSA and the prostate health index (PHI),
in men with a family history of prostate cancer: Results from a multicentre European study, the
PROMEtheuS project. BJU Int.: 2013; 112(3): 313-321 - Article
Lazzeri, M; Haese, A; De La Taille, A; Palou Redorta, J; McNicholas, T; Lughezzani, G; Scattoni,
V; Bini, V; Freschi, M; Sussman, A; Ghaleh, B; Le Corvoisier, P; Alberola Bou, J; Esquena Fernandez, S; Graefen, M; Guazzoni, G. Serum isoform [-2]proPSA derivatives significantly improve prediction of prostate cancer at initial biopsy in a total PSA range of 2-10 ng/ml: A multicentric european
study. Eur. Urol.: 2013; 63(6): 986-994 - Article
Losa, A; Gadda, GM; Lazzeri, M; Lughezzani, G; Cardone, G; Freschi, M; Lista, G; Larcher, A;
Nava, LD; Guazzoni, G. Complications and quality of life after template-assisted transperineal
prostate biopsy in patients eligible for focal therapy. Urology: 2013; 81(6): 1291-1296 - Article
Scattoni, V; Lazzeri, M; Lughezzani, G; De Luca, S; Passera, R; Bollito, E; Randone, D; Abdollah, F; Capitanio, U; Larcher, A; Lista, G; Gadda, GM; Bini, V; Montorsi, F; Guazzoni, G. Headto-head comparison of prostate health index and urinary PCA3 for predicting cancer at initial or repeat biopsy. J. Urol.: 2013; 190(2): 496-501 - Article
Villa, L; Buono, R; Fossati, N; Rigatti, P; Montorsi, F; Benigni, F; Hedlund, P. Effects by silodosin on the partially obstructed rat ureter in vivo and on human and rat isolated ureters. Br. J. Pharmacol.: 2013; 169(1): 230-238 - Article
CLINICAL
SERVICES
Pathology –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 315
HEAD OF UNIT: Claudio Doglioni*
CLINICAL UNIT COORDINATORS: Gianluigi Arrigoni, Giacomo Dell’Antonio, Massimo Freschi,
Maurilio Ponzoni, Isabella Sassi, Gianluca Taccagni, Maria Rosa Terreni
RESEARCHER: Francesca Sanvito
PHYSICIANS: Luca Albarello, Nathalie Rizzo
BIOLOGISTS: Maria Giulia Cangi, Lorenza Pecciarini
POST-DOCTORAL FELLOWS: Daniela Clavenna, Tiziana De Marino, Valeria De Pascale, Ilaria
Francaviglia, Greta Grassini, Gilda Magliacane
CONSULTANTS: Graziana Famoso, Gabriella Leone, Roberta Lucianò, Federica Pedica
TECHNICIANS: Mara Bertolazzi, Marina Brambilla, Roberto Cairella, Diana Ciscato, Elena Dal
Cin, Stefania Demasi, Barbara Di Ruvo, Patrizia Ferrari, Marilena Flore, Franco Galli, Stefano
Grassi, Laura Labbate, Camilla Lambiente, Anna Mauri, Michela Pensato, Martina Rocchi,
Graziella Santambrogio, Carlo Silva, Francesca Simonetti, Anna Talarico, Melissa Tonani
CYTOTECHNOLOGISTS: Teresa Carbone, Miriam Cosciotti, Grazia Lamonaca, Giulio Legnani,
Franca Toffolo
CONSULTANT CYTOTECHNOLOGIST: Loredana Alasio
Nuclear medicine –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 316
HEAD OF UNIT: Luigi Gianolli
CLINICAL UNIT COORDINATOR: Daniela Perani*
PHYSICIANS: Elena Busnardo, Carla Canevari, Flaviano Dosio, Federico Fallanca, Claudio
Landoni, Patrizia Magnani, Ursola Pajoro, Andrea Panzacchi, Gino Pepe, Maria Picchio, Ana
Maria Samanes Gajate, Paola Todeschini, Giovanna Vanoli
PHYSICISTS: Valentino Bettinardi, Maria Carla Gilardi, Luca Presotto, Annarita Savi
RADIOCHEMISTS: Valeria Masiello, Maria Grazia Minotti, Cristina Monterisi
PHD STUDENTS: Elena Maria Andreolli, Ada Apollaro, Flavio Mortarino, Isabella Raccagni
TECHNICIANS: Luca Brioschi, Patrizia Cerè, Antonia Compierchio, Paola Cordisco, Valeria
Crippa, Silvia Debbia, Andrea Fabro, Davide Gatti, Paola Lanzoni, Lorenzo Lecchi, Stefania
Longari, Claudia Maddè, Claudio Mannu, Raffaele Menichini, Giacomo Orlandi, Jacopo
Perego, Alice Piana, Riccardo Rigamonti, Lucia Rozza, Francesco Sudati, Mauro Vaghi,
Raffaele Vannulli
Radiotherapy –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 316
HEAD OF UNIT: Nadia Di Muzio
CLINICAL UNIT COORDINATOR: Angelo Bolognesi
PHYSICIANS: Saverio Beatrice, Genoveffa Berardi, Anna Chiara, Cesare Cozzarini, Aniko Maria
Deli, Italo Dell’Oca, Andrei Fodor, Marcella Pasetti, Paolo Passoni, Najla Slim
FELLOWS: Barbara Noris Chiorda, Flavia Zerbetto
TECHNICIANS: Fabio Baratto, Nietta Barricella, Roberta Bin, Alessandro Capelli, Alberta De
Leonardis, Caterina Fiordelisi, Laura Longoni, Marilena Martulano, Lidio Palumbo, Diana
Parutto, Vincenzo Sacco, Giovannella Salvadori, Andrea Sbalchiero, Simone Selli, Antonella
Soccio, Alessandro Tavilla, Andrea Viale
Laboratory medicine –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 317
HEAD OF DIVISION: Fernanda Dorigatti
HEADS OF UNIT: Ferruccio Ceriotti, Massimo Clementi*, Maurizio Ferrari*(*), Massimo Locatelli,
Laura Soldini
CLINICAL UNIT LEADERS: Paola Cichero, Stefania Del Rosso, Fulvio Ferrara, Anna Maria
Girardi, Cristina Ossi, Marina Pontillo, Sara Racca, Armando Soldarini, Silvana Viganò
313
CLINICAL SERVICES
PHYSICIANS: Enzo Boeri, Luciano Crippa, Rita Daverio, Annalisa Fattorini, Nicasio Mancini*,
Andrea Motta, Maria Grazia Patricelli, Serena Rolla, Loredana Tomassini, Mladen Trbos
BIOLOGISTS: Elena Bazzigaluppi, Sara Benedetti, Silvia Carletti, Anna Carobene, Arianna
Crepaldi, Nadia Ghidoli, Rossella Ieri, Rosanna Latino, Marcello Marinelli, Gabriella Passerini,
Elisabetta Pattarini, Flavia Piccini, Barbara Maria Pirola, Laura Seghezzi, Barbara Sioli, Ivana
Spiga, Annunziata Spina, Monica Zanussi
BIOENGINEER: Davide Alessio
CONSULTANTS: Emanuele Bosi *(#), Roberto Burioni *, Armando D’Angelo (#)
FELLOWS: Angela Brisci, Filippo Canducci, Nicola Clementi, Roberta Diotti, Chiara Di Resta,
Silvia Galbiati, Gisella Moreno, Diego Saita, Giuseppe Andrea Sautto, Laura Solforosi,
Stefania Stenirri
TECHNICIANS: Michela Sampaolo, Francesca Sampietro,(#), Nadia Soriani (*)
(*) reporting to the Center for Translational Genomics and BioInformatics
(#) reporting to the Division of Metabolic and Cardiovascular Sciences
Immunohematology and transfusion medicine –––––––––––––––––––––––––––––––––––––––– 317
HEAD OF UNIT: Fabio Ciceri
CLINICAL UNIT LEADERS: Lorena Barzizza, Laura Bellio
PHYSICIANS: Cinzia Bargiggia, Milena Coppola, Salvatore Gattillo, Lucia Malabarba, Simona
Malato, Raffaella Milani, Paola Ronchi, Michela Tassara
BIOLOGISTS: Oriana Perini, Cristina Tresoldi, Elisabetta Zino
CHEMIST: Benedetta Mazzi
TECHNICIANS: Cristina Parisi, Gabriele Torriani, Matilde Zambelli
Emergency medicine –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 318
HEAD OF UNIT: Michele Carlucci
DIRECTOR OF EMERGENCY MEDICINE PROGRAM: Marzia Spessot
CLINICAL UNIT COORDINATORS: Pietro Bisagni, Anna Borri, Roberto Faccincani, Maria Vittoria
Lavorato, Federica Mariani
PHYSICIANS: Aldo Beneduce, Giuseppe Capasso, Laura Ferrario, Manuela Fortunato, Federico
Furlan, Stefano Franchini, Simona Mauri, Enrico Ortolano, Cecilia Piani, Simona Rocchetti,
Maria Vittoria Taglietti, Valentina Tomajer
RESIDENTS: Nicola Bettera, Massimiliano Bissolati, Barbara Calcaterra, Giovanni Luigi Capretti,
Gabriella Cicenia, Sara Dal Farra, Andrea Duca, Luca Ferrante, Annalisa Gagliano, Paolo
Giovanni Gazzetta, Luca Ghirardelli, Cristina Gilardini, Barbara Guglielmi, Maria Lemma,
Alessandro Marinosci, Carlo Messina, Francesca Motta, Jacopo Nifosi, Francesca Pavesi,
Nicolò Pecorelli, Francesca Ratti, Maria Chiara Salandini, Eleonora Setti, Mirta Tiraboschi,
Anna Chiara Uccellatore
General intensive care –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 318
HEAD OF UNIT: Alberto Zangrillo*
CLINICAL UNIT COORDINATOR: Paolo Silvani
General anesthesia and neurointensive care Unit –––––––––––––––––––––––––––––––––––– 319
HEAD OF UNIT: Luigi Beretta*
CLINICAL UNIT COORDINATORS: Massimo Caldi, Daniela Giudici
* Professor at: Università Vita-Salute San Raffaele
CLINICAL SERVICES
Pathology
The OSR Pathology Unit provides complete diagnostic services in anatomic/surgical pathology
and autopsy service. Our Unit receives internal
samples from Ospedale San Raffaele Scientific
Institute and from several other hospital members
of the San Donato Group, with approximately
48.000 surgical pathology cases per year; cytological samples are 31.000 per year. We perform
also a same day diagnostic service for prostatic
biopsies, in which sampling, biopsy processing
and reporting are completed in about three hours.
Our activity encompasses all the wide variety of
pathology scenario. Moreover, approximately
1250 cases are reviewed either by our Unit when
patients, whose pathology specimens were originally examined elsewhere, are referred to OSR for
treatment or when other pathologists refer difficult
cases for second opinions. The number of specimens examined in surgical pathology has increased by almost 30% per year in the last 2
years.
The specialized medical and surgical practices at
San Raffaele Hospital are reflected in the diversity
of the specimen materials in our activity. Pathologists with particular interest and expertise in different specialty areas (e.g., Breast Pathology, Dermatopathology, Gastrointestinal&Hepatic Pathology, Gynecologic Pathology, Hematopathology,
Neuropathology, Pulmonary Pathology, Soft Tissue Pathology, and Urologic Pathology) interpret
and signout these cases. This approach ensures
excellent diagnostic interpretations, enhancing
collaboration with the specialized clinical services
present in San Raffaele Hospital. Diagnosis and
complementary services are provided by experienced and board-certified faculty and technical
staff, represented by 15 pathologists, 2 biologists, 26 technicians.
Many of our staff pathologists exert their specific
activity also when they are active members of Disease Units present at Our Istitutions, where the individual patients are specifically managed by a
team including different specialists.
Available tools include frozen sections, formalinfixed paraffin-embedded tissues, light microscopy, immunohistochemistry and immunoflu-
orescent staining, tissue micro- and macro-arrays, in-situ hybridization, and laser-capture assisted microdissection, with a continuously expanding and updated wide range of reagents.
The Oncologic Molecular Diagnostics Laboratory performs testing at the forefront of molecular
medicine using both molecular biology and molecular cytogenetics techinques. This rapidly
growing lab provides a wide range of diagnostic
tests for solid tumors and hematolymphoid malignancies for both OSR and external patients.
Many years of close interaction with our internal
pathologists and our referring physicians have
provided experience in understanding the diagnostic complexities (histotype evaluation, sample
selections, neoplastic component estimation) and
practical implications associated with these kind
of tests.
The molecular biology tests at present performed
include:
• KRAS, NRAS, EGFR, BRAF, PIK3CA, IDH1/2
genes mutation analysis
• MGMT methylation analysis
Methods and technologies utilized: standard
PCR, real-time PCR, Sanger sequencing, Pyrosequencing, Sequenom MassArray Genotyping.
We perform around 1,500 tests a year on genomic DNA extracted from a variety of specimen
types, including formalin-fixed paraffin-embedded
tissues, fresh and frozen tissues, cytological samples and body fluids.
The molecular cytogenetics tests include:
• HER2, FGFR1, MET,gene amplification
• ALK and ROS1 gene rearrangement
• EGFR gene copy number
• 1p and 19q chromosomal region deletions
• FISH analysis in hematological malignancies
(MYC, BCL1, BCL2, BCL6, BCL10, p53, ATM,
etc)
We perform around 1,000 tests a year on a variety of specimen types, including formalin-fixed
paraffin-embedded tissues, frozen tissues, cytological samples and blood.
Claudio Doglioni
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Nuclear medicine
The Nuclear Medicine Unit clinical activity may be
generally divided into two main fields: the “conventional” nuclear medicine activity, using single
photon emitting isotopes, such as 99m-Tc, 111In, and the positron emission tomography (PET)
nuclear medicine activity, using positron emitting
isotopes, such as 18F and 11C.
As for “conventional” nuclear medicine, the current main clinical indications are the cardiovascular evaluation of ischemic patients, the study of
skeletal system for both oncological and non-oncological disorders, the functional evaluation of
urinary, respiratory and endocrinal systems, and
the assessment of inflammatory and infectious
processes. For these examinations, the Centre is
provided with advanced equipment and techniques, including 3 SPECT and 1 SPECT/CT.
The principal clinical activity in Nuclear Medicine
Unit is PET imaging. In particular, in our Department, the integrated modality PET/computed tomography (PET/CT) scan is commonly used. The
Nuclear Medicine Unit / PET Centre provided with
the most advanced technology. Currently, there
are two cyclotrons (18 MeV and 11 MeV), 4
PET/CT tomographs, five radiochemical laboratories equipped with hot cells and automatic systems for the synthesis of PET radiopharmaceuticals, according to “Norme di Buona Preparazione
dei Radiofarmaci in Medicina Nucleare (NBPMN)”.
The main clinical indication of PET imaging is the
evaluation of oncological patients. PET/CT is particularly used in different phases of diagnostic
processes, including the staging and the re-staging of the disease, the planning of radiotherapy
treatment, the monitoring and the evaluation of
therapies. In addition to oncology, by using
PET/CT, cardiac and neurological studies are also
performed, and particularly for the evaluation of
coronary diseases and degenerative disorders,
respectively.
Luigi Gianolli
Radiotherapy
Radiotherapy (RT) currently represents one of the
main treatments in oncologic patients, 60-80% of
whom are candidate to RT as exclusive treatment
( radical or palliative) ,or as adjuvant treatment after surgery . In particular today Radiotherapy
could be used as a valid alternative to surgery or
chemotherapy in selected groups of patients.
In our Department we treat up to 2000 new patients/year and all cancer types except for paediatric disease . The installation in 2004 of the new
generation of Linac allowed us to improve the quality of our treatments by means of Intensity Modulated Radiation Therapy ( IMRT) and Image Guided
Radiation Therapy (IGRT). Thanks to greater precision in delivering the curative dose in our clinical activity we are able to use hypofractionated schemes
for the principal tumor pathologies, reducing the total length of the treatment. The use of metabolic imaging by means of PET/CT, permits an improved
identification of disease sites with elevated cellular
activity. These images are useful, both for better
definition of treatment volume and in particular the
identification of sub-volumes to which higher radiation doses can be delivered thanks to the treatment technique known as SIB (Simultaneous Integrated Boost). MR imaging has been shown to be
particularly effective in the identification of organs at
risk during the planning process, and of specific
characteristics of the target to be irradiated (especially in the head/neck, prostate and brain districts). These treatment modalities have permitted
the improvement of the therapeutic index as well as
the decrease of iatrogenic sequels with a concurrent reduction in the number of treatment sessions.
PET/TC and MR repeated during the radiation treatment, in combination with daily IGRT, can address
tumor volume and positional changes, as well as
other pathologic changes and deformations occurring during the RT treatment course, introducing
the potential for individualized plan adaptation
based on imaging feedback, including bulky residual disease, tumor progression, and physiological
changes that occur during the treatment course,
thereby enabling better normal tissue sparing while
allowing radical target doses with the possibility of
maximising local control. Finally for lesions subject
to organ motion (e.g. lung, liver , pancreatic lesions)
four-Dimensional PET/TC allows more accurate
target definition, limiting dose to nearby organs at
risk. In addition, advances in dose calculation algorithms have allowed for more accurate dosimetry in heterogeneous media, and intensity modulated and arc/ helical delivery techniques can help
spare organs at risk.
Nadia Di Muzio
CLINICAL SERVICES
Laboratory medicine
Diagnostica e Ricerca San Raffaele (Laboraf) is
the Laboratory Medicine Unit that provides clinical
laboratory services to the San Raffaele Hospital.
Laboraf is organized as a department that includes: Clinical Chemistry - Toxicology - Immunochemistry, Haematology (in conjunction with the
Immunohematology and Transfusion Medicine
Service), Coagulation, Microbiology - Virology and
Serology, Clinical Molecular Biology and Cytogenetic, Autoimmune diseases. All these sectors are
highly specialized and continuously evolving. In
2013 Laboraf produced about 7.2 millions of clinical analyses, for a total of 990,000 patients. In
2013 21 new types of tests were introduced in
various fields (microbiology and virology, molecular biology, new biomarkers and toxicology tests).
Besides clinical services Laboraf produces also
research work in the field of Standardization in
Clinical Chemistry, in Microbiology and Virology.
1. Standardization in Clinical Chemistry. Development of a reference measurement procedure for
the determination of Pancreatic Lipase catalytic
activity. Definition of reference intervals and biological variation.
2. Microbiology. Molecular diagnosis of sepsis;
molecular diagnosis of systemic fungal infections;
analysis of gut and oral microbiome in different
clinical conditions.
3. Virology. Molecular diagnosis of infections by
viral agents of acute respiratory diseases (myxoviruses, coronaviruses, respiratory syncytial virus
and viruses identified recently in infants with acute
respiratory diseases); molecular monitoring of antiviral therapies, including detection of drug-resistant variants; in vitro characterization of neutralizing anti-HCV and anti-Influenza A human monoclonal antibodies; cross-reacting and neutralizing
human monoclonal antibody directed against the
HCV\E2 protein; Hepatitis C virus (HCV)-driven
stimulation of subfamily-restricted natural IgM antibodies in mixed cryoglobulinemia; antiviral Response Elicited by Anti-Idiotype Monoclonal Antibodies.
Laboraf collaborates also in research projects
with the research Center for Translational Genomics and BioInformatics, with the research Division of metabolic and cardiovascular sciences
and with the Department of Internal and specialistic medicine.
Fernanda Dorigatti
Immunohematology and transfusion medicine service
The Hospital San Raffaele (OSR) Immunohematology and Transfusion Medicine Service (ITMS)
provides clinical services to support OSR patients
in need of blood component therapy, cellular therapy, therapeutic apheresis, and specialized laboratory diagnostics. This ISO 9002 Certified unit
collects and prepares the blood components and
cellular therapy products used in patient care at
the OSR, maintain an accredited Immunohematology Reference Lab and provides education in
the field of Transfusion Medicine. ITMS is conducting a project, funded by Regione Lombardia,
on the appropriateness of blood transfusion.
The ITMS is subdivided into three distinct subunits, each responsible for a particular process:
Blood Donation Center
The blood donation center subunit is responsible
for the collection and testing of blood to be transfused into patients at the San Raffaele Hospital. It
is responsible for handling all aspects of donor recruitment for whole blood products, apheresis
products, the auto-transfusion program and therapeutic phlebotomy. During 2013 were presented
to make a donation 8376 candidates of these only 7021 have donated. 5550 were donations of
whole blood and 1471 were donations by
apheresis, plateletpheresis or plasmapheresis.
Therapeutic Apheresis and Cellular Therapy
The Therapeutic Apheresis and Cellular Therapy
subunit is responsible for collecting and processing hematopoietic stem cells and performs the
necessary diagnostic testing required for bone
marrow transplantation procedures. The lab supplies hematopoietic stem cells and relevant cells
in support of clinical trials for allogenic bone marrow and peripheral blood transplantation and offers a Stem Cell Cryo Banking service for autologous and allogeneic bone marrow products.
Bone Marrow from qualified donors is collected in
accordance and recognition of the Italian Bone
Marrow Donor Registry (IBMDR). Therapeutic
apheresis procedures to treat patients with neurologic and blood diseases, including photopheresis, red cell and plasma exchange procedures
are also performed routinely.
The unit of therapeutic apheresis is part of the
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bone marrow transplants program and underwent
in October 2013, accreditation Jacie inspection.
During 2013, were performed 2010 apheresis for
the collection of autologous or allogeneic
hematopoietic stem cells. The procedures of
photopheresis were 150 while the plasma exchange procedures were 70.
Clinical Laboratory Diagnostics
The Clinical Laboratory Diagnostics subunit in-
cludes the following specialized laboratories: Immunohematology, Hematology, Flow Cytometry,
Hematological Molecular Biology and an EFI Certified and accredited HLA tissue typing laboratory.
New technologies such as genetic red blood cell
typing are being investigated. A special emphasis
is given to onco-hematologic malignancies and to
the development of minimal-residual-disease
tools.
Fabio Ciceri
Emergency medicine
In 2013 the Emergency Department of San Raffaele Hospital provided care for 62,157 patients.
1,346 of the triaged patients were given a red
code (that is, to be seen immediately in the resuscitation area). 11,610 of them were given a yellow
code (that is, to be seen within 30 minutes of arrival). The largest amount of them (46,988) were
given lower priority (green code, that means to be
seen within 1 hour of arrival). Only 2,213 of them
were given a white code (that is, patients whose
conditions are not true emergencies). In 2013 we
have seen 20,498 patients with medical problems, 15,800 with surgical problems and 10,628
with minor trauma. 7,450 children have been
treated in the pediatric area. In the dedicated area
for obstetrics 5,186 women received treatment.
10,449 patients, after initial evaluation, were admitted to different wards for further investigations
and treatments.
In 2013 608 patients received surgery in the
Emergency room.
Major trauma (patient with multiple injuries) is
treated by a trauma team who has been trained
using the principles taught in the internationally
recognized Advanced Trauma Life Support
course. Medical emergencies are treated as
taught in the Advanced Life Support and Trauma
Advanced Life Support courses.
Some members of the Emergency Room staff are
ALS and ATLS instructors and such courses are
regularly held in our Hospital every year.
Staff members receive Emergency Medicine upto-date meetings every two weeks.
Medical students from Università Vita-Salute are
trained on application of classical emergency
medicine principals in a human and supportive
patient environment.
In 2013 physicians attended the following meetings and courses: American Heart Association
Dallas, USA, November) Il medico d’urgenza nella
gestione della syndrome coronarica acuta (Torino,
April) 14th European Congress of Trauma 6 Emergency Surgery (Lyon, May), Trauma Update (Milano, December), Medical Response to Major Incidents (Stockholm, August), Mass Fatality Incidents (Rome, May), FIMEUC National Meeting
(Rome, November). International Conference on
Health Care System Engeneering (Milan, May),
24th SMART (May); Le urgenze neurologiche:
dalla diagnosi alla terapia (Milan, October), Campus in medicina d’Urgenza (Torino, April).
Michele Carlucci
General intensive care
Our General Intensive Care Unit (ICU) admitted
436 patients and the occupational rate was 86%
with a mean ICU lenght of stay 6.2+9.8) days.
Overall, patients were 61 y, 56% had acute kidney injury and mean SAP II was 35+20.8.
Nearly 60% of these patients required an advanced intensive treatment, while the others were
subjects who needed a postoperative monitoring
after major elective surgery.
In order to guarantee the care for in-hospital or territorial emergencies and to improve availability to-
wards patients from lower level hospitals, we have
recently developed a strategy to optimize ICU admissions, improving an early postoperative care in
recovery room for the postoperative patients.
The principal critical illnesses managed in our unit
(sum is >100% because more than one diagnosis
was allowed) included:
• Trauma (10% of intensive treatments). As front
line of a 2nd level hospital in Milan county, general ICU accept a significant number of subject
involved in traffic and work accident;
CLINICAL SERVICES
• Respiratory failure (77% of intensive treatments).
Primary and secondary ARDS (acute respiratory
distress syndrome) are frequent and undesirable evolutions of pneumonia or systemic sepsis, especially in immunocompromised patients
like in autoimmune pathology or after transplantation;
• Cardiovascular failure or multiple organ dysfunctions (43.8 % of intensive treatments). Patients
rescued from cardiac arrest or with cardiac congestive failure;
• Cardiocirculatory arrests (8.4%)
• Septic shock (47% of intensive treatments). Severe evolution of sepsis, complication in patients submitted to major surgery or transplantation;
• Neurologic, neuromuscolar and neurophysiological disorders;
• Intensive treatment in potential donor patients.
In our general ICU we can provide a wide range of
therapeutic options and protocols for these specific pathologies, updated to the last international
guidelines: the newest strategies in mechanical
ventilation including extracorporeal life support,
updated antibiotic therapy, hypothermic therapy
post cardiac arrest and developments in continuous renal replacement therapy.
Improving ultrasound use in ICU through an intensive staff training leaded to the organization of a
centralized system for ultrasound central line
catheter positioning for more than 600 in-hospital
patients/year.
The general ICU physicians also provide a medical emergency team (MET) 24 hours a day, which
is involved in hospital emergencies and consulting. This kind of organization allows MET to safely
perform non invasive ventilation treatment for mild
or chronic respiratory failure in non intensive areas. The same ICU staff provides all the non-cardiosurgery emergency surgical procedures.
Our ICU promotes and supports a significant
number of teaching courses (BLSD, ALS, ATLS,
maxiemergency, sepsis campaign diffusion, CVC
ultrasound positioning, non invasive ventilation).
Alberto Zangrillo
General anaesthesia and neurointensive care Unit
Neurointensive Care is a 6 beds unit. 300 patients are admitted every year, 50% from the Casualty Department (severe head injury, stroke and
subarachnoid haemorrhage) and 50% from the
Neurosurgery Unit (tumor, vascular). 20 patients
with brain death are treated and 12 of them become organ donors.
The Head and Neck Anaesthesia Staff provides
for general anaesthesia in neurosurgical, interventional neuroradiology, ENT and ophthalmic surgery for approximately 3,000 cases per year and
for conscious sedations in children and adults
(1,000 cases per year) submitted to diagnostic or
therapeutic procedures in Neuroradiology.
The General Anaesthesia Staff provides for
anaesthesia in the Surgical Department (Gastroenterology, Haepatology, Endocrine, Pancreatic), Orthopaedics, Obstetrics and Gynaecology,
Plastic Surgery (approximately 20,000 cases/per
year). Outside the O.R. sedation and anaesthesia
are performed for diagnostic and therapeutic interventions in Gastroenterology.
A staff is dedicated to the treatment of the postoperative acute pain and chronical neoplastic
pain (“Hospital without Pain” Committee).
Luigi Beretta
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Selected publications
Abdollah, F; Suardi, N; Cozzarini, C; Gallina, A; Capitanio, U; Bianchi, M; Sun, M; Fossati, N;
Passoni, NM; Fiorino, C; Di Muzio, N; Karakiewicz, PI; Rigatti, P; Montorsi, F; Briganti, A. Selecting the Optimal Candidate for Adjuvant Radiotherapy After Radical Prostatectomy for Prostate
Cancer: A Long-term Survival Analysis. Eur. Urol.: 2013; 63(6): 998-1008 - Article
Aiuti, A; Biasco, L and Scaramuzza, S; Ferrua, F; Cicalese, MP; Baricordi, C; Dionisio, F; Calabria, A; Giannelli, S; Castiello, MC; Bosticardo, M; Evangelio, C; Assanelli, A; Casiraghi, M;
Di Nunzio, S; Callegaro, L; Benati, C; Rizzardi, P; Pellin, D; Di Serio, C; Schmidt, M; Von Kalle, C;
Gardner, J; Mehta, N; Neduva, V; Dow, DJ; Galy, A; Miniero, R; Finocchi, A; Metin, A; Banerjee, P;
Orange, J; Galimberti, S; Valsecchi, MG; Biffi, A; Montini, E; Villa, A; Ciceri, F; Roncarolo, MG
and Naldini, L. Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich
Syndrome. Science: 2013; 341(6148): 123351 - Article
Argentieri, MC; Pilla, D; Vanzati, A; Lonardi, S; Facchetti, F; Doglioni, C; Parravicini, C; Cattoretti, G.
Antibodies are forever: A study using 12-26-year-old expired antibodies. Histopathology: 2013;
63(6): 869-876 - Article
Azzeroni, R; Maggio, A; Fiorino, C; Mangili, P; Cozzarini, C; De Cobelli, F; Di Muzio, NG; Calandrino, R. Biological optimization of simultaneous boost on intra-prostatic lesions (DILs): Sensitivity to TCP parameters. Phys. Med.: 2013; 29(6): 592-598 - Article
Hartmann, S; Döring, C; Jakobus, C; Rengstl, B; Newrzela, S; Tousseyn, T; Sagaert, X; Ponzoni,
M; Facchetti, F; de Wolf-Peeters, C; Steidl, C; Gascoyne, R; Küppers, R; Hansmann, ML. Nodular
lymphocyte predominant hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma - endpoints of a spectrum of one disease?. PLoS One: 2013; 8(11): e78812 - Article
Biffi, A and Montini, E; Lorioli, L; Cesani, M; Fumagalli, F; Plati, T; Baldoli, C; Martino, S; Calabria, A; Canale, S; Benedicenti, F; Vallanti, G; Biasco, L; Leo, S; Kabbara, N; Zanetti, G; Rizzo,
WB; Mehta, NA; Cicalese, MP; Casiraghi, M; Boelens, JJ; Del Carro, U; Dow, DJ; Schmidt, M;
Assanelli, A; Neduva, V; Di Serio, C; Stupka, E; Gardner, J; von Kalle, C; Bordignon, C; Ciceri,
F; Rovelli, A; Roncarolo, MG; Aiuti, A; Sessa, M; Naldini, L. Lentiviral Hematopoietic Stem Cell
Gene Therapy Benefits Metachromatic Leukodystrophy. Science: 2013; 341(6148): 1233158 - Article
Briganti, A; Joniau, S; Gandaglia, G; Cozzarini, C; Sun, M; Tombal, B; Haustermans, K; Hinkelbein, W; Shariat, SF; Karakiewicz, PI; Montorsi, F; Van Poppel, H; Wiegel, T. Patterns and predictors of early biochemical recurrence after radical prostatectomy and adjuvant radiation therapy in
men with pT3N0 prostate cancer: implications for multimodal therapies. Int. J. Radiat. Oncol. Biol.
Phys.: 2013; 87(5): 960-967 - Article
Broggi, S; Cantone, MC; Chiara, A; Di Muzio, N; Longobardi, B; Mangili, P; Veronese, I. Application of failure mode and effects analysis (FMEA) to pretreatment phases in tomotherapy. J. Appl.
Clin. Med. Phys: 2013; 14(5): 265-277 - Article
Brunetto, E and Ferrara, AM; Rampoldi, F; Talarico, A; Dal Cin, E; Grassini, G; Spagnuolo, L;
Sassi, I; Ferro, A; Veronica Cuorvo, L; Barbareschi, M; Piccinin, S; Maestro, R; Pecciarini, L; Doglioni, C; Cangi, MG. CDC25A protein stability represents a previously unrecognized target of
HER2 signaling in human breast cancer: Implication for a potential clinical relevance in trastuzumab
treatment. Neoplasia: 2013; 15(6): 579-590 - Article
Caganova, M; Carrisi, C and Varano, G; Mainoldi, F; Zanardi, F; Germain, PL; George, L; Alberghini,
F; Ferrarini, L; Talukder, AK; Ponzoni, M; Testa, G; Nojima, T; Doglioni, C; Kitamura, D; Toellner,
KM; Su, IH; Casola, S. Germinal center dysregulation by histone methyltransferase EZH2 promotes
lymphomagenesis. J Clin Invest: 2013; 123(12): 5009-5022 - Article
Calandrino, R; Ardu, V; Corletto, D; Del Vecchio, A; Origgi, D; Signorotto, P; Spinelli, A; Tosi, G;
Bolognesi, A; Cariati, M; Kluzer, A; Muscarella, S. Evaluation of second cancer induction risk by CT
follow-up in oncological long-surviving patients. Health Phys.: 2013; 104(1): 1-8 - Article
Canducci, F; Ceresola, ER; Saita, D; Castagna, A; Gianotti, N; Underwood, M; Burioni, R; Lazzarin, A; Clementi, M. In vitro phenotypes to elvitegravir and dolutegravir in primary macrophages
and lymphocytes of clonal recombinant viral variants selected in patients failing raltegravir. J. Antimicrob. Chemother.: 2013; 68(11): 2525-2532 - Article
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Carbone, A; Spina, M; Gloghini, A; Ponzoni, M; Doglioni, C; Tirelli, U. Nodular lymphocyte predominant Hodgkin lymphoma with non-invasive or early invasive growth pattern suggests an early
step of the disease with a highly favorable outcome. Am. J. Hematol.: 2013; 88(2): 161-162 - Letter
Carobene, A; Braga, F; Roraas, T; Sandberg, S; Bartlett, WA. A systematic review of data on biological variation for alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transferase.
Clin. Chem. Lab. Med.: 2013; 51(10): 1997-2007 - Article
Carobene, A; Guerra, E; Ceriotti, F. A mechanism-based way to evaluate commutability of control
materials for enzymatic measurements. The example of gamma-glutamyltransferase. Clin. Chim. Acta: 2013; 424: 153-158 - Article
Castellucci, P; Picchio, M. 11C-Choline PET/CT and PSA kinetics. Eur. J. Nucl. Med. Mol. Imaging:
2013; 40(1 Suppl): 36-40 - Article
Casucci, M; Nicolis di Robilant, B; Falcone, L; Camisa, B; Norelli, M; Genovese, P; Gentner,
B; Gullotta, F; Ponzoni, M; Bernardi, M; Marcatti, M; Saudemont, A; Bordignon, C; Savoldo, B;
Ciceri, F; Naldini, L; Dotti, G; Bonini, C; Bondanza, A. CD44v6-targeted T cells mediate potent
antitumor effects against acute myeloid leukemia and multiple myeloma. Blood: 2013; 122(20):
3461-3472 - Article
Casucci, M; Perna, SK; Falcone, L; Camisa, B; Magnani, Z; Bernardi, M; Crotta, A; Tresoldi,
C; Fleischhauer, K; Ponzoni, M; Gregori, S; Caligaris-Cappio, F; Ciceri, F; Bordignon, C; Cignetti, A; Bondanza, A and Bonini, C. Graft-versus-leukemia effect of HLA-haploidentical centralmemory t-cells expanded with leukemic APCs and modified with a suicide gene. Mol. Ther.: 2013;
21(2): 466-475 - Article
Cattaneo, GM; Passoni, P; Longobardi, B; Slim, N; Reni, M; Cereda, S; Di Muzio, N; Calandrino, R. Dosimetric and clinical predictors of toxicity following combined chemotherapy and moderately hypofractionated rotational radiotherapy of locally advanced pancreatic adenocarcinoma. Radiother. Oncol.: 2013; 108(1): 66-71 - Article
Clementi, N and Mancini, N; Castelli, M; Clementi, M; Burioni, R. Characterization of epitopes
recognized by monoclonal antibodies: Experimental approaches supported by freely accessible
bioinformatic tools. Drug Discov. Today: 2013; 18(41556): 464-471 - Review
Dvir, R and Mancini, N; Assanelli, A; Racca, S; Rolla, S; Clementi, N; Piemontese, S; Ciceri,
F; Burioni, R; Clementi, M. Acute respiratory distress in a neutropenic febrile patient after
hematopoietic cell transplantation. J. Clin. Virol.: 2013; 57(1): 1-4 - Note
Fayad, HJ; Lamare, F; Le Rest, CC; Bettinardi, V; Visvikis, D. Generation of 4-dimensional CT images based on 4-dimensional PET-derived motion fields. J. Nucl. Med.: 2013; 54(4): 631-638 - Article
Fellin, F; Azzeroni, R; Maggio, A; Lorentini, S; Cozzarini, C; Di Muzio, N; Fiorino, C; Calandrino,
R; Schwarz, M. Helical tomotherapy and intensity modulated proton therapy in the treatment of
dominant intraprostatic lesion: A treament planning comparison. Radiother. Oncol.: 2013; 107(2):
207-212 - Article
Folli, C; Consonni, D; Spessot, M; Salvini, L; Velati, M; Ranzani, G; Maiavacca, R; Monzani, V. Diagnostic role of copeptin in patients presenting with chest pain in the emergency room. Eur. J. Intern. Med.: 2013; 24(2): 189-193 - Article
Garibotto, V; Tettamanti, M; Marcone, A; Florea, I; Panzacchi, A; Moresco, R; Virta, JR; Rinne, J;
Cappa, SF; Perani, D. Cholinergic activity correlates with reserve proxies in Alzheimer’s disease.
Neurobiol. Aging: 2013; 34(11): e13-e18 - Article
Gianotti, N; Galli, L; Salpietro, S; Cernuschi, M; Bossolasco, S; Maillard, M; Spagnuolo, V;
Canducci, F; Clementi, M; Lazzarin, A; Castagna, A. Virological rebound in human immunodeficiency virus-infected patients with or without residual viraemia: Results from an extended follow-up.
Clin. Microbiol. Infect.: 2013; 19(12): E542-E544 - Article
Giovacchini, G; Picchio, M; Garcia-Parra, R; Mapelli, P; Briganti, A; Montorsi, F; Gianolli, L;
Messa, C. [(11)C]Choline Positron Emission Tomography/Computerized Tomography for Early Detection of Prostate Cancer Recurrence in Patients with Low Increasing Prostate Specific Antigen. J.
Urology: 2013; 189(1): 105-110 - Article
Goudy, K and Aydin, D; Barzaghi, F; Gambineri, E; Vignoli, M; Mannurita, SC; Doglioni, C; Ponzoni, M; Cicalese, MP; Assanelli, A; Tommasini, A; Brigida, I; Dellepiane, RM; Martino, S; Olek,
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S; Aiuti, A; Ciceri, F; Roncarolo, MG; Bacchetta, R. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin. Immunol.: 2013; 146(3): 248-261 Article
Hess Michelini, R and Manzo, T; Sturmheit, T; Basso, V; Rocchi, M; Freschi, M; Listopad, J;
Blankenstein, T; Bellone, M and Mondino, A. Vaccine-instructed intratumoral IFN-g enables regression of autochthonous mouse prostate cancer in allogeneic T-cell transplantation. Cancer Res.:
2013; 73(15): 4641-4652 - Article
Ichihara, K; Ceriotti, F; Tam, TH; Sueyoshi, S; Poon, PMK; Thong, ML; Higashiuesato, Y; Wang, X;
Kataoka, H; Matsubara, A; Shiesh, SC; Muliaty, D; Kim, JH; Watanabe, M; Lam, CWK; Siekmann,
L; Lopez, JB; Panteghini, M. The Asian project for collaborative derivation of reference intervals: (1)
strategy and major results of standardized analytes. Clin. Chem. Lab. Med.: 2013; 51(7): 14291442 - Article
Ichihara, K; Ceriotti, F; Kazuo, M; Huang, YY; Shimizu, Y; Suzuki, H; Kitagawa, M; Yamauchi, K;
Hayashi, S; Tsou, CC; Yamamoto, Y; Ishida, S; Leong, L; Sano, M; Lim, HS; Suwabe, A; Woo, HY;
Kojima, K; Okubo, Y. The Asian project for collaborative derivation of reference intervals: (2) results of
non-standardized analytes and transference of reference intervals to the participating laboratories on
the basis of cross-comparison of test results. Clin. Chem. Lab. Med.: 2013; 51(7): 1443-1457 - Article
Klunk, WE; Perani, D. Amyloid and neurodegeneration: Converging and diverging paths. Neurology:
2013; 81(20): 1728-1729 - Comment
Maffi, P and Balzano, G; Ponzoni, M; Nano, R; Sordi, V; Melzi, R; Mercalli, A; Scavini, M;
Esposito, A; Peccatori, J; Cantarelli, E; Messina, C; Bernardi, M; Del Maschio, A; Staudacher,
C; Doglioni, C; Ciceri, F; Secchi, A; Piemonti, L. Autologous Pancreatic Islet Transplantation in
Human Bone Marrow. Diabetes: 2013; 62(10): 3523-3531 - Article
Maggio, A; Carillo, V; Cozzarini, C; Perna, L; Rancati, T; Valdagni, R; Gabriele, P; Fiorino, C. Impact of the radiotherapy technique on the correlation between dose-volume histograms of the bladder wall defined on MRI imaging and dose-volume/surface histograms in prostate cancer patients.
Phys. Med. Biol.: 2013; 58(7): N115-N123 - Article
Mancini, N; Burioni, R; Sanguinetti, M; Clementi, M. Risks of “blind” automated identification systems in medical microbiology. J. Clin. Microbiol.: 2013; 51(11): 3911 - Letter
Mapelli, P; Mangili, G; Picchio, M; Gentile, C; Rabaiotti, E; Giorgione, V; Spinapolice, EG;
Gianolli, L; Messa, C; Candiani, M. Role of 18F-FDG PET in the management of gestational trophoblastic neoplasia. Eur. J. Nucl. Med. Mol. Imaging: 2013; 40(4): 505-513 - Article
Marinova, M; Altinier, S; Caldini, A; Passerini, G; Pizzagalli, G; Brogi, M; Zaninotto, M; Ceriotti, F;
Plebani, M. Multicenter evaluation of hemoglobin A1c assay on capillary electrophoresis. Clin. Chim.
Acta: 2013; 424: 207-211 - Article
Melloni, G; Samanes Gajate, AM; Sestini, S; Gallivanone, F; Bandiera, A; Landoni, C; Muriana,
P; Gianolli, L; Zannini, P. New positron emission tomography derived parameters as predictive factors for recurrence in resected stage i non-small cell lung cancer. Eur. J. Surg. Oncol.: 2013; 39(11):
1254-1261 - Article
Passoni, P; Fiorino, C; Slim, N; Ronzoni, M; Ricci, V; Di Palo, S; De Nardi, P; Orsenigo, E;
Tamburini, A; De Cobelli, F; Losio, C; Iacovelli, NA; Broggi, S; Staudacher, C; Calandrino, R;
Di Muzio, N. Feasibility of an adaptive strategy in preoperative radiochemotherapy for rectal cancer
with image-guided tomotherapy: Boosting the dose to the shrinking tumor. Int. J. Radiat. Oncol. Biol.
Phys.: 2013; 87(1): 67-72 - Article
Passoni, P; Reni, M; Cattaneo, GM; Slim, N; Cereda, S; Balzano, G; Castoldi, R; Longobardi,
B; Bettinardi, V; Gianolli, L; Gusmini, S; Staudacher, C; Calandrino, R; Di Muzio, N. Hypofractionated image-guided IMRT in advanced pancreatic cancer with simultaneous integrated boost to
infiltrated vessels concomitant with capecitabine: A phase i study. Int. J. Radiat. Oncol. Biol. Phys.:
2013; 87(5): 1000-1006 - Article
Picchio, M; Piert, M. Prostate cancer imaging. Eur. J. Nucl. Med. Mol. Imaging: 2013; 40(Suppl 1):
S1-S4 - Editorial
Ponzoni, M; Govi, S; Licata, G; Mappa, S; Giordano Resti, A; Politi, LS; Spagnuolo, L; Di Cairano, E; Doglioni, C; Ferreri, AJM. A reappraisal of the diagnostic and therapeutic management of
CLINICAL SERVICES
uncommon histologies of primary ocular adnexal lymphoma. Oncologist: 2013; 18(7): 876-884 Review
Raccosta, L and Fontana, R; Maggioni, D; Lanterna, C; Villablanca, EJ;Paniccia, A; Musumeci,
A; Chiricozzi, E; Trincavelli, ML; Daniele, S; Martini, C; Gustafsson, J; Doglioni, C; Feo, SG; Leiva,
A; Ciampa, MG; Mauri, L; Sensi, C; Prinetti, A; Eberini, I; Mora, M; Bordignon, C; Steffensen, KR;
Sonnino, S; Sozzani, S; Traversari, C and Russo, V. The oxysterol-cxcr2 axis plays a key role in the
recruitment of tumor-promoting neutrophils. J. Exp. Med.: 2013; 210(9): 1711-1728 - Article
Ranzani, M; Cesana, D and Bartholomae, CC; Sanvito, F; Pala, M; Benedicenti, F; Gallina, P;
Sergi Sergi, L; Merella, S; Bulfone, A; Doglioni, C; Von Kalle, C; Kim, YJ; Schmidt, M; Tonon, G;
Naldini, L; Montini, E. Lentiviral vector-based insertional mutagenesis identifies genes associated
with liver cancer. Nat. Methods: 2013; 10(2): 155-161 - Article
Russo, V and Pilla, L; Lunghi, F; Crocchiolo, R; Greco, R; Ciceri, F; Maggioni, D; Fontana, R;
Mukenge, S; Rivoltini, L; Rigamonti, G; Mercuri, SR; Nicoletti, R; Del Maschio, A; Gianolli, L;
Fazio, F; Marchianò, A; Di Florio, A; Maio, M; Salomoni, M; Gallo-Stampino, C; Del Fiacco, M; Lambiase, A; Coulie, PG; Patuzzo, R; Parmiani, G; Traversari, C; Bordignon, C; Santinami, M and Bregni, M. Clinical and immunologic responses in melanoma patients vaccinated with MAGE-A3genetically modified lymphocytes. Int. J. Cancer: 2013; 132(11): 2557-2566 - Article
Soliman, C; Casiraghi, M; Antonioli, G; Ciceri, F; Roncarolo, MG; Callegaro, L; Aiuti, A. Percorso assistenziale nel bambino ADA SCID sottoposto a terapia genica con cellule staminali
ematopoietiche: Il ruolo dell’infermiere di ricerca. Pediatric Reports: 2013; 5(SUPPL.1): 127-128 Article
Todisco, E; Ciceri, F; Oldani, E; Boschini, C; Mico, C; Vanlint, MT; Donnini, I; Patriarca, F; Alessandrino, PE; Bonifazi, F; Arcese, W; Barberi, W; Marenco, P; Terruzzi, E; Cortelazzo, S; Santarone, S;
Proia, A; Corradini, P; Tagliaferri, E; Falcioni, S; Irrera, G; Dallanegra, L; Castagna, L; Santoro, A;
Camboni, A; Sacchi, N; Bosi, A; Bacigalupo, A; Rambaldi, A. The CIBMTR score predicts survival of
AML patients undergoing allogeneic transplantation with active disease after a myeloablative or reduced intensity conditioning: A retrospective analysis of the Gruppo Italiano Trapianto di Midollo Osseo. Leukemia: 2013; 27(10): 2086-2091 - Letter
323
CLINICAL SERVICES
WHO Collaborating Centre for Integrated Laboratory
Strengthening on Tuberculosis, WHO Supranational
Reference Laboratory and ESCMID collaborative Centre
Tuberculosis (TB) causes nearly 2 million deaths
each year. Current TB treatment is long, and drug
resistance (DR) continues to increase globally
with multiple and extensively drug-resistant (MDR
and XDR) TB being major threats to TB Control
worldwide.
In this context, the Global TB Department of the
World Health Organization (WHO) gives high priority to the prevention of the emergence of additional drug resistance, for which the laboratory surveillance of drug resistance represents an essential
tool in evaluating and monitoring quality and effectiveness of TB control programmes.
In May 2013, on the basis of the successful collaborative activities with the WHO Stop TB department, and of the acknowledged experience in
providing technical assistance in the field of mycobacteriology the Fondazione Centro San Raffaele was reconfirmed by the WHO and the Italian
Ministry of Health “WHO Collaborating Centre for
Integrated Laboratory Strengthening on Tuberculosis” (WHOCC, ITA98). This recognition is in addition to the status of member of Supranational
Reference Laboratory Network.
The activities performed by the Center during
2013 cover three main areas:
Laboratory training courses on laboratory techniques and management for laboratory staff from
high incidence Countries and for laboratory consultants, with the aim to increase the knowledge
and skills of laboratory staff in assisted Countries.
Five training courses were offered no different
topics including a national training in advanced
mycobacteriology. We have organized an advanced national training course on mycobacteriology in Milan and supported the molecular diagnostics implementation in Ethiopia, Ivory Coast
and Burkina Faso.
Planning and supporting high burden Countries in
conducting Operational Research on new diagnostic tools for drug resistant TB detection. This
study gathers answers to scientific research
questions and will serve as a basis for improving
fast detection and treatment of drug resistant tuberculosis cases. Two studies are ongoing: the
first aiming at the implementation of new regimens
for shorter treatment of drug resistant tuberculosis
(in collaboration with the University of Brescia
WHOcc and other international partners), the second on the rational use of new diagnostics in several high burden Countries. In support to the
Global Program for TB drug resistance surveillance we have optimized a protocol based on
Next Generation Sequencing for fast detection of
mutation. The protocol was used to detect the
pharmacoresistance to floroquinolones and
pyrazinamide on 1400 TB strains collected in
Pakistan and Bangladesh.
Laboratory technical assistance to Countries: in
order to contribute to meet the local national TB
programme’s objectives in the area, we provide
long term support in the implementation of laboratory activities at countries level according to the
WHO global plan guidelines. Through co-funding
by WHO and other international partners, the
Centre has performed 14 monitoring and assessment visits providing technical assistance and supervision to the TB programs and the TB National
Reference laboratories in 10 Countries (Mozambique, Ethiopia, Nigeria, Albania, Kosovo, Turkey,
Iraq, Burkina Faso, Ivory Coast). We have participated to national review missions of the National
TB Control program in Pakistan and in Nigeria.
In addition, in the role of ESCMID center and
supported by the ESCMID short visit exchange
program, 4 scientists were hosted by EBPU for
completion of their research projects. Main focus
of the four ESCMID sponsored observerships
was the typing of multidrug resistant pathogens
emerging worldwide.
Daniela Maria Cirillo
Head, WHO Collaborating Centre ITA 98
TB Supranational Reference laboratory
PUBLICATIONS
325
PUBLICATIONS
P.1. Abbas, AK and Benoist, C and Bluestone, JA and Campbell, DJ and Ghosh, S and Hori, S and Jiang, S and
Kuchroo, VK and Mathis, D and Roncarolo, MG and
Rudensky, A and Sakaguchi, S and Shevach, EM and Vignali, DAA and Ziegler, SF. Regulatory T cells: Recommendations to simplify the nomenclature. Nat. Immunol.: 2013;
14(4): 307-308 - Letter
P.2. Abdollah, F; Abdo, A; Sun, M; Schmitges, J; Tian, Z;
Briganti, A; Shariat, SF; Perrotte, P; Montorsi, F;
Karakiewicz, PI. Pelvic lymph node dissection for prostate
cancer: Adherence and accuracy of the recent guidelines.
Int. J. Urol.: 2013; 20(4): 405-410 - Article
IF 2012: 1,734
P.3. Abdollah, F and Boorjian, S; Cozzarini, C; Suardi, N;
Sun, M; Fiorino, C; Di Muzio, N; Karakiewicz, PI; Montorsi, F; Karnes, RJ; Briganti, A. Survival following biochemical recurrence after radical prostatectomy and adjuvant radiotherapy in patients with prostate cancer: The impact of competing causes of mortality and patient stratification. Eur. Urol.: 2013; 64(4): 557-564 - Article
IF 2012: 10,476
P.4. Abdollah, F; Cozzarini, C; Sun, M; Suardi, N; Gallina,
A; Passoni, NM; Bianchi, M; Tutolo, M; Fossati, N; Nini, A; Dell’Oglio, P; Salonia, A; Karakiewicz, P; Montorsi, F; Briganti, A. Assessing the most accurate formula to
predict the risk of lymph node metastases from prostate
cancer in contemporary patients treated with radical
prostatectomy and extended pelvic lymph node dissection. Radiother. Oncol.: 2013; 109(2): 211-216 - Article
IF 2012: 4,520
P.5. Abdollah, F and Gandaglia, G; Thuret, R; Schmitges, J;
Tian, Z; Jeldres, C; Passoni, NM; Briganti, A; Shariat,
SF; Perrotte, P; Montorsi, F; Karakiewicz, PI; Sun, M. Incidence, survival and mortality rates of stage-specific bladder cancer in United States: A trend analysis. Cancer Epidemiol.: 2013; 37(3): 219-225 - Article
IF 2012: 2,232
P.6. Abdollah, F; Suardi, N; Capitanio, U; Gallina, A; Sun,
M; Villa, L; Scattoni, V; Bianchi, M; Tutolo, M; Fossati,
N; Karakiewicz, P; Rigatti, P; Montorsi, F; Briganti, A.
Spatial distribution of positive cores improves the selection
of patients with low-risk prostate cancer as candidates for
active surveillance. BJU Int.: 2013; 112(4): E234-E242 Article
IF 2012: 3,046
P.7. Abdollah, F; Suardi, N; Cozzarini, C; Gallina, A; Capitanio, U; Bianchi, M; Sun, M; Fossati, N; Passoni, NM;
Fiorino, C; Di Muzio, N; Karakiewicz, PI; Rigatti, P; Montorsi, F; Briganti, A. Selecting the Optimal Candidate for
Adjuvant Radiotherapy After Radical Prostatectomy for
Prostate Cancer: A Long-term Survival Analysis. Eur. Urol.:
2013; 63(6): 998-1008 - Article
IF 2012: 10,476
P.8. Abdollah, F; Suardi, N; Gallina, A; Bianchi, M; Tutolo,
M; Passoni, N; Fossati, N; Sun, M; dell’Oglio, P; Salonia, A; Karakiewicz, PI; Rigatti, P; Montorsi, F; Briganti,
A. Extended pelvic lymph node dissection in prostate cancer: A 20-year audit in a single center. Ann. Oncol.: 2013;
24(6): 1459-1466 - Article
IF 2012: 7,384
P.9. Abdollah, F; Sun, M; Suardi, N; Gallina, A; Capitanio,
U; Bianchi, M; Tutolo, M; Fossati, N; Castiglione, F;
Freschi, M; Karakiewicz, P; Rigatti, P; Montorsi, F; Briganti, A. Presence of positive surgical margin in patients
with organ-confined prostate cancer equals to extracapsular extension negative surgical margin. A plea for TNM
staging system reclassification. Urol. Oncol.: 2013; 31(8):
1497-1503 - Article
IF 2012: 3,647
P.10. Abdollah, F; Sun, M; Suardi, N; Gallina, A; Tutolo, M;
Passoni, N; Bianchi, M; Salonia, A; Colombo, R; Rigatti, P; Karakiewicz, PI; Montorsi, F; Briganti, A. A novel
tool to assess the risk of urinary incontinence after nervesparing radical prostatectomy. BJU Int.: 2013; 111(6):
905-913 - Article
IF 2012: 3,046
P.11. Abraham, AB; Bronstein, R; Chen, EI; Koller, A; Ronfani,
L; Maletic-Savatic, M; Tsirka, SE. Members of the high
mobility group B protein family are dynamically expressed
in embryonic neural stem cells. Proteome Sci.: 2013;
11(1): 18 - Article
IF 2012: 2,420
P.12. Abutalebi, J. Bilingualism beyond languages: The impact of bilingualism upon the brain. Comment on “The
bilingual brain: Flexibility and control in the human cortex”
by Buchweitz and Prat.. Phys. Life Rev.: 2013; 10(4): 444445 - Comment
P.13. Abutalebi, J; Della Rosa, PA; Castro Gonzaga, AK;
Keim, R; Costa, A; Perani, D. The role of the left putamen
in multilingual language production. Brain Lang.: 2013;
125(3): 307-315 - Article
IF 2012: 3,386
P.14. Abutalebi, J; Della Rosa, PA; Ding, G; Weekes, B;
Costa, A; Green, DW. Language proficiency modulates
the engagement of cognitive control areas in multilinguals.
Cortex: 2013; 49(3): 905-911 - Article
IF 2012: 6,161
P.15. Acquati, F; Lualdi, M; Bertilaccio, S; Monti, L; Turconi,
G; Fabbri, M; Grimaldi, A; Anselmo, A; Inforzato, A; Collotta, A; Cimetti, L; Riva, C; Gribaldo, L; Ghia, P; Taramelli, R.
Loss of function of Ribonuclease T2, an ancient and phylogenetically conserved RNase, plays a crucial role in ovarian
tumorigenesis. Proc. Natl. Acad. Sci. U. S. A.: 2013;
110(20): 8140-8145 - Article
IF 2012: 9,737
P.16. Adorno, M; Sikandar, S; Mitra, SS; Kuo, A; Nicolis Di
Robilant, B; Haro-Acosta, V; Ouadah, Y; Quarta, M; Rodriguez, J; Qian, D; Reddy, VM; Cheshier, S; Garner, CC;
Clarke, MF. Usp16 contributes to somatic stem-cell defects in Down’s syndrome. Nature: 2013; 501(7467): 380384 - Article+F12
IF 2012: 38,597
P.17. Agathangelidis, A; Ntoufa, S; Stamatopoulos, K. B Cell
receptor and antigens in CLL. Adv. Exp. Med. Biol.: 2013;
792: 1-24 - Article
IF 2012: 1,825
P.18. Agnelli, G; Buller, HR; Cohen, A; Curto, M; Gallus, AS;
Johnson, M; Masiukiewicz, U; Pak, R; Thompson, J;
Raskob, GE; Weitz, JI; for the AMPLIFY Investigators.
Oral apixaban for the treatment of acute venous thromboembolism. N. Engl. J. Med.: 2013; 369(9): 799-808 Article
IF 2012: 51,658
P.19. Agnelli, G; Buller, HR; Cohen, A; Curto, M; Gallus, AS;
Johnson, M; Porcari, A; Raskob, GE; Weitz, JI; for the
AMPLIFY-EXT Investigators. Apixaban for Extended
Treatment of Venous Thromboembolism. N. Engl. J. Med.:
2013; 368(8): 699-708 - Article
IF 2012: 51,658
P.20. Agosta, F; Canu, E; Stojkovic, T; Pievani, M; Tomic, A;
Sarro, L; Dragasevic, N; Copetti, M; Comi, G; Kostic, VS;
Filippi, M. The topography of brain damage at different
stages of parkinson’s disease. Hum. Brain Mapp.: 2013;
34(11): 2798-2807 - Article
IF 2012: 6,878
P.21. Agosta, F; Canu, E; Valsasina, P; Riva, N; Prelle, A;
Comi, G; Filippi, M. Divergent brain network connectivity
in amyotrophic lateral sclerosis. Neurobiol. Aging: 2013;
34(2): 419-427 - Article
IF 2012: 6,166
P.22. Agosta, F; Caso, F; Filippi, M. Dementia and neuroimaging. J. Neurol.: 2013; 260(2): 685-691 - Article
IF 2012: 3,578
327
PUBLICATIONS
P.23. Agosta, F; Galantucci, S; Canu, E; Cappa, SF; Magnani, G; Franceschi, M; Falini, A; Comi, G; Filippi, M.
Disruption of structural connectivity along the dorsal and
ventral language pathways in patients with nonfluent and
semantic variant primary progressive aphasia: A DT MRI
study and a literature review. Brain Lang.: 2013; 127(2):
157-166 - Article
IF 2012: 3,386
P.24. Agosta, F; Kostic, VS; Davidovic, K; Kresojević, N;
Sarro, L; Svetel, M; Stanković, I; Comi, G; Klein, C; Filippi, M. White matter abnormalities in Parkinson’s disease
patients with glucocerebrosidase gene mutations. Mov.
Disord.: 2013; 28(6): 772-778 - Article
IF 2012: 4,558
P.25. Agosta, F; Sala, S; Valsasina, P; Meani, A; Canu, E;
Magnani, G; Cappa, SF; Scola, E; Quatto, P; Horsfield,
MA; Falini, A; Comi, G; Filippi, M. Brain network connectivity assessed using graph theory in frontotemporal dementia. Neurology: 2013; 81(2): 134-143 - Article
IF 2012: 8,249
P.26. Agretti, P and Segni, M; De Marco, G; Ferrarini, E; Di
Cosmo, C; Corrias, A; Weber, G; Larizza, D; Calcaterra, V;
Pelizzo, MR; Cesaretti, G; Vitti, P; Tonacchera, M. Prevalence of activating thyrotropin receptor and Gsa gene mutations in paediatric thyroid toxic adenomas: A multicentric
Italian study. Clin. Endocrinol.: 2013; 79(5): 747-749 - Letter
IF 2012: 3,396
P.27. Agricola, E and Slavich, M; Tufaro, V; Fisicaro, A; Oppizzi, M; Melissano, G; Bertoglio, L; Marone, E; Civilini,
E; Margonato, A; Chiesa, R. Prevalence of thoracic ascending aortic aneurysm in adult patients with known abdominal aortic aneurysm: An echocardiographic study. Int.
J. Cardiol.: 2013; 168(3): 3147-3148 - Letter
IF 2012: 5,509
P.28. Aiuti, A; Biasco, L and Scaramuzza, S; Ferrua, F; Cicalese, MP; Baricordi, C; Dionisio, F; Calabria, A;
Giannelli, S; Castiello, MC; Bosticardo, M; Evangelio,
C; Assanelli, A; Casiraghi, M; Di Nunzio, S; Callegaro,
L; Benati, C; Rizzardi, P; Pellin, D; Di Serio, C; Schmidt,
M; Von Kalle, C; Gardner, J; Mehta, N; Neduva, V; Dow,
DJ; Galy, A; Miniero, R; Finocchi, A; Metin, A; Banerjee, P;
Orange, J; Galimberti, S; Valsecchi, MG; Biffi, A; Montini,
E; Villa, A; Ciceri, F; Roncarolo, MG and Naldini, L.
Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome. Science: 2013;
341(6148): 123351 - Article
IF 2012: 31,027
P.29. Aiuti, A; Cossu, G; de Felipe, P; Galli, MC; Narayanan,
G; Renner, M; Stahlbom, A; Schneider, CK; Voltz-Girolt, C.
The committee for advanced therapies’ of the European
Medicines Agency reflection paper on management of
clinical risks deriving from insertional mutagenesis. Hum.
Gene Ther. Clin. Dev.: 2013; 24(2): 47-54 - Article
IF 2012: No Impact Factor
P.30. Alasker, A and Meskawi, M; Sun, M; Ismail, S; Hanna, N;
Hansen, J; Tian, Z; Bianchi, M; Perrotte, P; Karakiewicz,
PI. A contemporary update on rates and management of
toxicities of targeted therapies for metastatic renal cell carcinoma. Cancer Treat. Rev.: 2013; 39(4): 388-401 - Review
IF 2012: 6,024
P.31. Alberici, L; Roth, L; Sugahara, KN; Agemy, L; Kotamraju, VR; Teesalu, T; Bordignon, C; Traversari, C; Rizzardi,
GP; Ruoslahti, E. De Novo design of a tumor-penetrating
peptide. Cancer Res.: 2013; 73(2): 804-812 - Article
IF 2012: 8,650
P.32. Alessandrino, EP and Porta, MGD and Malcovati, L and
Jackson, CH and Pascutto, C; Bacigalupo, A; Teresa van
Lint, M; Falda, M; Bernardi, M; Onida, F; Guidi, S; Iori, AP;
Cerretti, R; Marenco, P; Pioltelli, P; Angelucci, E; Oneto, R;
Ripamonti, F; Rambaldi, A; Bosi, A and Cazzola, M; and
on behalf of Gruppo Italiano Trapianto di Midollo Osseo
(GITMO). Optimal timing of allogeneic hematopoietic stem
cell transplantation in patients with myelodysplastic syndrome. Am. J. Hematol.: 2013; 88(7): 581-588 - Article
IF 2012: 4,138
P.33. Alfano, M; Graziano, F; Genovese, L; Poli, G.
Macrophage polarization at the crossroad between hiv-1
infection and cancer development. Arterioscler. Thromb.
Vasc. Biol.: 2013; 33(6): 1145-1152 - Article
IF 2012: 6,338
P.34. Alfieri, O; De Bonis, M. Tricuspid valve surgery for severe tricuspid regurgitation. Heart: 2013; 99(3): 149-150 Comment
P.35. Alfieri, O; Pozzoli, A. Mitral valve surgery in octogenarians: Insights and perspectives. J. Cardiothorac. Vasc.
Anesth.: 2013; 27(2): 201-202 - Comment
P.36. Amato, MP; Langdon, D; Montalban, X; Benedict, RHB;
Deluca, J; Krupp, LB; Thompson, AJ; Comi, G. Treatment
of cognitive impairment in multiple sclerosis: Position paper. J. Neurol.: 2013; 260(6): 1452-1468 - Review
IF 2012: 3,578
P.37. Amato, N; Riva, N; Cursi, M; Martins-Silva, A; Martinelli, V; Comola, M; Fazio, R; Comi, G; Leocani, L.
Different Frontal Involvement in ALS and PLS Revealed by
Stroop Event-Related Potentials and Reaction Times.
Front. Aging Neurosci.: 2013; 5: 82 - Article
IF 2012: 5,224
P.38. Amendola, M; Giustacchini, A; Gentner, B; Naldini, L.
A double-switch vector system positively regulates transgene expression by endogenous microRNA expression
(miR-ON vector). Mol. Ther.: 2013; 21(5): 934-946 - Article
IF 2012: 7,041
P.39. Ammirati, E; Cristell, N; Cianflone, D; Vermi, AC; Marenzi, G; De Metrio, M; Uren, NG; Hu, D; Ravasi, T; Maseri, A; Cannistraci, CV. Questing for circadian dependence
in ST-segment-elevation acute myocardial infarction: a
multicentric and multiethnic study. Circ. Res.: 2013;
112(10): e110-e114 - Article
IF 2012: 11,861
P.40. Ammirati, E; Musca, F; Oliva, F; Garascia, A; Pacher, V;
Verde, A; Cipriani, M; Moreo, A; Martinelli, L; Frigerio, M.
Levosimendan reverted severe pulmonary hypertension in
one patient on waiting list for heart transplantation. Int. J.
Cardiol.: 2013; 168(4): 4518-4519 - Letter
IF 2012: 5,509
P.41. Amodio, G and Mugione, A; Sanchez, AM; Viganò,
P; Candiani, M; Somigliana, E; Roncarolo, MG; PaninaBordignon, P and Gregori, S. HLA-G expressing DC-10
and CD4(+) T cells accumulate in human decidua during
pregnancy. Hum. Immunol.: 2013; 74(4): 406-411 - Article
IF 2012: 2,298
P.42. Amzulescu, MS; Slavich, M; Florian, A; Goetschalckx,
K; Voigt, JU. Does two-dimensional image reconstruction
from three-dimensional full volume echocardiography improve the assessment of left ventricular morphology and
function?. Echocardiography: 2013; 30(1): 55-63 - Article
IF 2012: 1,261
P.43. Anelli, T; van Anken, E. Missing Links in Antibody Assembly Control. Int. J. Cell Biol.: 2013; 2013: 606703 Review
IF 2012: No Impact Factor
P.44. Annoni, A and Cantore, A; Della Valle, P; Goudy, K;
Akbarpour, M; Russo, F; Bartolaccini, S; D’Angelo, A;
Roncarolo, MG and Naldini, L. Liver gene therapy by
lentiviral vectors reverses anti-factor IX pre-existing immunity in haemophilic mice. EMBO Mol. Med.: 2013; 5(11):
1684-1697 - Article
IF 2012: 7,795
P.45. Annoni, A and Goudy, K; Akbarpour, M; Naldini, L;
Roncarolo, MG. Immune responses in liver-directed
PUBLICATIONS
lentiviral gene therapy. Transl. Res.: 2013; 161(4): 230240 - Review
IF 2012: 3,490
P.46. Annovazzi, P and Tomassini, V; Bodini, B; Boffa, L; Calabrese, M; Cocco, E; Cordioli, C; De Luca, G; Frisullo, G;
Gallo, A; Malucchi, S; Paolicelli, D; Pesci, I; Radaelli, M;
Ragonese, P; Roccatagliata, L; Tortorella, C; Vercellino, M;
Zipoli, V; Gasperini, C; Rodegher, M; Solaro, C. A crosssectional, multicentre study of the therapeutic management of multiple sclerosis relapses in Italy. Neurol. Sci.:
2013; 34(2): 197-203 - Article
IF 2012: 1,412
P.47. Antelmi, E; Coccagna, G; Ferini-Strambi, L; Marelli, S;
Provini, F. ‘Restless bladder’ and the boundaries of the
restless legs syndrome. Eur. J. Neurol.: 2013; 20(11):
e128 - Letter
IF 2012: 4,162
P.48. Antonini, A; Abbruzzese, G; Ferini-Strambi, L; Tilley, B;
Huang, J; Stebbins, GT; Goetz, CG; Barone, P; Bandettini
di Poggio, M; Fabbrini, G; Di Stasio, F; Tinazzi, M; Bovi, T;
Ramat, S; Meoni, S; Pezzoli, G; Canesi, M; Martinelli, P;
Maria Scaglione, CL; Rossi, A; Tambasco, N; Santangelo,
G; Picillo, M; Morgante, L; Morgante, F; Quatrale, R; Sensi, M; Pilleri, M; Biundo, R; Nordera, G; Caria, A; Pacchetti, C; Zangaglia, R; Lopiano, L; Zibetti, M; Zappia, M; Nicoletti, A; Quattrone, A; Salsone, M; Cossu, G; Murgia, D;
Albanese, A; Del Sorbo, F. Validation of the Italian version
of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale. Neurol. Sci.: 2013; 34(5): 683-687 Article
IF 2012: 1,412
P.49. Anzalone, N; Essig, M; Lee, SK; Dorfler, A; Ganslandt,
O; Combs, SE; Picozzi, P. Optimizing contrast-enhanced
magnetic resonance imaging characterization of brain
metastases: Relevance to stereotactic radiosurgery. Neurosurgery: 2013; 72(5): 691-701 - Review
IF 2012: 2,532
P.50. Anzalone, N; Scarabino, T; Venturi, C; Cristaudo, C; Tartaro, A; Scotti, G; Zimatore, D; Floris, R; Carriero, A; Longo, M; Cirillo, M; Cova, MA; Gatti, S; Voth, M; Colosimo,
C. Cerebral neoplastic enhancing lesions: Multicenter, randomized, crossover intraindividual comparison between
gadobutrol (1.0 M) and gadoterate meglumine (0.5 M) at
0.1 mmol Gd/kg body weight in a clinical setting. Eur. J.
Radiol.: 2013; 82(1): 139-145 - Article
IF 2012: 2,512
P.51. Apollonio, B; Scielzo, C; Bertilaccio, MT; Ten Hacken, E; Scarfò, L; Ranghetti, P; Stevenson, F; Packham,
G; Ghia, P; Muzio, M and Caligaris-Cappio, F. Targeting
B-cell anergy in chronic lymphocytic leukemia. Blood:
2013; 121(19): 3879-3888 - Article
IF 2012: 9,060
P.52. Aprile, G; Avellini, C; Reni, M; Mazzer, M; Foltran, L;
Rossi, D; Cereda, S; Iaiza, E; Fasola, G; Piga, A. Biglycan
expression and clinical outcome in patients with pancreatic
adenocarcinoma. Tumour Biol.: 2013; 34(1): 131-137 Article
IF 2012: 2,518
P.53. Arcidiacono, PG; Baillie, J. Investigating branch duct intraductal papillary mucinous neoplasms: Is large-volume
lavage cytology the wave of the future?. Gastrointest. Endosc.: 2013; 77(5): 736-738 - Comment
P.54. Argentieri, MC; Pilla, D; Vanzati, A; Lonardi, S; Facchetti,
F; Doglioni, C; Parravicini, C; Cattoretti, G. Antibodies are
forever: A study using 12-26-year-old expired antibodies.
Histopathology: 2013; 63(6): 869-876 - Article
IF 2012: 2,857
P.55. Aricò, D; Raggi, A; Siragusa, M; Zucconi, M; Ferri, R.
Restless legs syndrome as the presenting symptom of
multiple myeloma. J. Clin. Sleep Med.: 2013; 9(4): 383385 - Article
IF 2012: 2,928
P.56. Atanur, SS; Diaz, AG; Maratou, K; Sarkis, A; Rotival, M;
Game, L; Tschannen, MR; Kaisaki, PJ; Otto, GW; Ma,
MCJ; Keane, TM; Hummel, O; Saar, K; Chen, W; Guryev,
V; Gopalakrishnan, K; Garrett, MR; Joe, B; Citterio, L;
Bianchi, G; McBride, M; Dominiczak, A; Adams, DJ;
Serikawa, T; Flicek, P; Cuppen, E; Hubner, N; Petretto, E;
Gauguier, D; Kwitek, A; Jacob, H; Aitman, TJ. Genome
sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat. Cell: 2013;
154(3): 691-703 - Article
IF 2012: 31,957
P.57. Athappan, G; Patvardhan, E; Tuzcu, EM; Svensson, LG;
Lemos, PA; Fraccaro, C; Tarantini, G; Sinning, JM; Nickenig, G; Capodanno, D; Tamburino, C; Latib, A; Colombo, A; Kapadia, SR. Incidence, predictors, and outcomes
of aortic regurgitation after transcatheter aortic valve replacement: Meta-analysis and systematic review of literature. J. Am. Coll. Cardiol.: 2013; 61(15): 1585-1595 - Review
IF 2012: 14,086
P.58. Auner, HW; Moody, AM; Ward, TH; Kraus, M; Milan, E;
May, P; Chaidos, A; Driessen, C; Cenci, S; Dazzi, F; Rahemtulla, A; Apperley, JF; Karadimitris, A; Dillon, N. Combined Inhibition of p97 and the Proteasome Causes Lethal
Disruption of the Secretory Apparatus in Multiple Myeloma
Cells. PLoS ONE: 2013; 8(9): e74415 - Article
IF 2012: 3,730
P.59. Autores/miembros del Grupo de Trabajo: Camm, AJ;
Lip, GY; Caterina, RD; Savelieva, I; Atar, D; Hohnloser, SH;
Hindricks, G; Kirchhof, P; Comité de la ESC de Guías para
la Práctica Clínica (CGPC): Bax, JJ; Baumgartner, H; Ceconi, C; Dean, V; Deaton, C; Fagard, R; Funck-Brentano,
C; Hasdai, D; Hoes, A; Kirchhof, P; Knuuti, J; Kolh, P; McDonagh, T; Moulin, C; Popescu, BA; Reiner, Z; Sechtem,
U; Anton Sirnes, P; Tendera, M; Torbicki, A; Vahanian, A;
Windecker, S; Revisores del documento: Vardas, P; Al-Attar, N; Alfieri, O; Angelini, A; Blömstrom-Lundqvist, C;
Colonna, P; De Sutter, J; Ernst, S; Goette, A; Gorenek, B;
Hatala, R; Heidbüchel, H; Heldal, M; Dalby Kristensen, S;
Kolh, P; Le Heuzey, JY; Mavrakis, H; Mont, L; Perrone Filardi, P; Ponikowski, P; Prendergast, B; Rutten, FH; Schotten, U; Van Gelder, IC; Verheugt, FW. Updated detailed
ESC guidelines for the management of atrial fibrillation,
2012 [Actualización detallada de las guías de la ESC para
el manejo de la fibrilación auricular de 2012: Actualización
de las guías de la Sociedad Europea de Cardiología (ESC)
para el manejo de la fibrilación auricular de 2010 Elaborada en colaboración con la Asociación Europea del Ritmo
Cardiaco]. Rev. Esp. Cardiol.: 2013; 66(1): 54.e1-54.e24
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IF 2012: 3,204
P.60. Avan, A and Pacetti, P and Reni, M; Milella, M; Vasile, E;
Mambrini, A; Vaccaro, V; Caponi, S; Cereda, S; Peters,
GJ; Cantore, M; Giovannetti, E. Prognostic factors in gemcitabine-cisplatin polychemotherapy regimens in pancreatic cancer: XPD-Lys751Gln polymorphism strikes back. Int.
J. Cancer: 2013; 133(4): 1016-1022 - Article
IF 2012: 6,198
P.61. Azzeroni, R; Maggio, A; Fiorino, C; Mangili, P; Cozzarini, C; De Cobelli, F; Di Muzio, NG; Calandrino, R.
Biological optimization of simultaneous boost on intra-prostatic lesions (DILs): Sensitivity to TCP parameters. Phys.
Med.: 2013; 29(6): 592-598 - Article
IF 2012: 1,167
P.62. Azzolini, C; Sansoni, G; Donati, S; Battaglia Parodi, M;
Oum, MA; Vinciguerra, R; Tartaglia, V; Semeraro, F; Virgili,
G. Clinical analysis of macular edema with new software
for SD-OCT imaging. Eur. J. Ophthalmol.: 2013; 23(6):
899-904 - Article
IF 2012: 0,912
P.63. Baccari, P; Nifosi, J; Ghirardelli, L; Staudacher, C.
Short- and mid-term outcome after laparoscopic repair of
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large incisional hernia. Hernia: 2013; 17(5): 567-572 - Article
IF 2012: 1,693
P.64. Bachi, A; Dalle-Donne, I; Scaloni, A. Redox Proteomics:
Chemical Principles, Methodological Approaches and Biological/Biomedical Promises. Chem. Rev.: 2013; 113(1):
596-698 - Review
IF 2012: 41,298
P.65. Bagaglio, S; Messina, E; Uberti-Foppa, C; Merli, M;
Della Torre, L; Lazzarin, A; Hasson, H; Morsica, G. Reversion of naturally occurring high-level resistance mutations to NS3 protease inhibitors in two treatment-naive individuals infected with hepatitis C virus. J. Antimicrob.
Chemother.: 2013; 68(6): 1448-1450 - Letter
IF 2012: 5,338
P.66. Balakrishnan, N; Tortoli, E; Engel, SL; Breitschwerdt,
EB. Isolation of a novel strain of Mycobacterium iranicum
from a woman in the United States. J. Clin. Microbiol.:
2013; 51(2): 705-707 - Article
IF 2012: 4,068
P.67. Baldi, S; Bonnet, F; Laville, M; Morgantini, C; Monti, L;
Hojlund, K; Ferrannini, E; Natali, A; on behalf of the RISC
Investigators. Influence of Apolipoproteins on the Association Between Lipids and Insulin Sensitivity: A cross-sectional analysis of the RISC Study. Diabetes Care: 2013;
36(12): 4125-4131 - Article
IF 2012: 7,735
P.68. Balzano, G; Maffi, P; Nano, R; Zerbi, A; Venturini, M;
Melzi, R; Mercalli, A; Magistretti, P; Scavini, M; Castoldi, R; Carvello, M; Braga, M; Del Maschio, A; Secchi,
A; Staudacher, C; Piemonti, L. Extending indications for
islet autotransplantation in pancreatic surgery. Ann. Surg.:
2013; 258(2): 210-218 - Article
IF 2012: 6,329
P.69. Bandello, F; La Spina, C; Iuliano, L; Fogliato, G;
Battaglia Parodi, M. Review and perspectives on pharmacological vitreolysis. Ophthalmologica: 2013; 230(4):
179-185 - Review
IF 2012: 1,412
P.70. Bandello, F; Lattanzio, R; Zucchiatti, I; Del Turco, C.
Pathophysiology and treatment of diabetic retinopathy. Acta Diabetol.: 2013; 50(1): 1-20 - Review
IF 2012: 4,631
P.71. Bandello, F; Spina, CL; Battaglia Parodi, M. Management of macular edema from branch retinal vein occlusions. Expert Rev. Ophthalmol.: 2013; 8(5): 469-473 - Review
IF 2012: No Impact Factor
P.72. Barbagli, G; Montorsi, F; Guazzoni, G; Larcher, A;
Fossati, N; Sansalone, S; Romano, G; Buffi, N; Lazzeri,
M. Ventral oral mucosal onlay graft urethroplasty in nontraumatic bulbar urethral strictures: Surgical technique and
multivariable analysis of results in 214 patients. Eur. Urol.:
2013; 64(3): 440-447 - Article
IF 2012: 10,476
P.73. Barbanti, M; Yang, TH; Rodes Cabau, J; Tamburino, C;
Wood, DA; Jilaihawi, H; Blanke, P; Makkar, RR; Latib, A;
Colombo, A; Tarantini, G; Raju, R; Binder, RK; Nguyen, G;
Freeman, M; Ribeiro, HB; Kapadia, S; Min, J; Feuchtner,
G; Gurtvich, R; Alqoofi, F; Pelletier, M; Ussia, GP; Napodano, M; De Brito, FS; Kodali, S; Norgaard, BL; Hansson,
NC; Pache, G; Canovas, SJ; Zhang, H; Leon, MB; Webb,
JG; Leipsic, J. Anatomical and procedural features associated with aortic root rupture during balloon-expandable
transcatheter aortic valve replacement. Circulation: 2013;
128(3): 244-253 - Article
IF 2012: 15,202
P.74. Barbero, M; Cescon, C; Tettamanti, A; Leggero, V;
Macmillan, F; Coutts, F; Gatti, R. Myofascial trigger points
and innervation zone locations in upper trapezius muscles.
BMC Musculoskelet. Disord.: 2013; 14: 179 - Article
IF 2012: 1,875
P.75. Barda, B; Zepherine, H; Rinaldi, L; Cringoli, G; Burioni,
R; Clementi, M; Albonico, M. Mini-FLOTAC and KatoKatz: Helminth eggs watching on the shore of lake Victoria.
Parasites Vectors: 2013; 6(1): 220 - Article
IF 2012: 3,246
P.76. Barda, BD; Rinaldi, L; Ianniello, D; Zepherine, H; Salvo,
F; Sadutshang, T; Cringoli, G; Clementi, M; Albonico, M.
Mini-FLOTAC, an Innovative Direct Diagnostic Technique
for Intestinal Parasitic Infections: Experience from the Field.
PLoS Neglected Tropical Diseases: 2013; 7(8): e2344 Article
IF 2012: 4,569
P.77. Barile, L; Landoni, G; Pieri, M; Ruggeri, L; Maj, G; Nigro Neto, C; Pasin, L; Cabrini, L; Zangrillo, A. Cardiac index assessment by the pressure recording analytic
method in critically ill unstable patients after cardiac surgery. J. Cardiothorac. Vasc. Anesth.: 2013; 27(6): 11081113 - Article
IF 2012: 1,448
P.78. Baroncini, D; Spagnolo, F; Sarro, L; Comi, G; Volonté, MA. A complex case of anti-GAD antibody-related syndrome treated with Rituximab. Neurol. Sci.: 2013; 34(10):
1847-1849 - Letter
IF 2012: 1,412
P.79. Bartoli, A; Esposito, G; D’Angeli, L; Chaabane, L; Terreno, E. MRI and PET compatible bed for direct co-registration in small animals. IEEE Trans Nucl Sci: 2013; 60(3):
1596-1602 - Article
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P.80. Bartoli, E; Tettamanti, A; Farronato, P; Caporizzo, A;
Moro, A; Gatti, R; Perani, D; Tettamanti, M. The disembodiment effect of negation: negating action-related sentences attenuates their interference on congruent upper
limb movements. J. Neurophysiol.: 2013; 109: 17821792 - Article
IF 2012: 3,301
P.81. Basso, L; Pescatori, M; La Torre, F; Destefano, I; Pulvirenti D’Urso, A; Infantino, A; Amato, A; AECO Group.
Emerging technologies in coloproctology: results of the
Italian Society of Colorectal Surgery Logbook of Adverse
Events. Tech. Coloproctol.: 2013; 17(2): 207-211 - Article
IF 2012: 1,538
P.82. Battaglia Parodi, M; De Benedetto, U; Vergallo, S;
Knutsson, KA; Bandello, F; Lanzetta, P; Iacono, P. Intravitreal bevacizumab for retinal neovascularizations associated with myelinated nerve fibers. J. Ocul. Pharmacol. Ther.:
2013; 29(4): 442-443 - Article
IF 2012: 1,293
P.83. Battaglia Parodi, M; Iacono, P; Mansour, A; De
Benedetto, U; Knutsson, KA; Bandello, F; Ziemssen, F;
Ness, T; Dodwell, D. Intravitreal bevacizumab for
juxtafoveal choroidal neovascularization secondary to multifocal choroiditis. Retina: 2013; 33(5): 953-956 - Article
IF 2012: 2,825
P.84. Battaglia Parodi, M; Iacono, P; Menchini, F; Sheth, S;
Polini, G; Pittino, R; Bandello, F. Intravitreal bevacizumab
versus ranibizumab for the treatment of retinal angiomatous
proliferation. Acta Ophthalmol.: 2013; 91(3): 267-273 - Article
IF 2012: 2,345
P.85. Battaglia Parodi, M; Iacono, P; Papayannis, A; Kontadakis, S; Cascavilla, ML; Zucchiatti, I; Bandello, F. Intravitreal bevacizumab for extrafoveal choroidal neovascularization secondary to pathologic myopia. Retina: 2013;
33(3): 593-597 - Article
IF 2012: 2,825
P.86. Battaglia Parodi, M; Iacono, P; Papayannis, A; Kontadakis, SD; Cascavilla, M; Pierro, L; Gagliardi, M;
Bandello, F. Intravitreal ranibizumab for pigment epithelium
detachment with subfoveal occult choroidal neovascular-
PUBLICATIONS
ization: A prospective 24-month case series. Am. J. Ophthalmol.: 2013; 155(1): 103-108 - Article
IF 2012: 3,631
P.87. Bechi, M; Spangaro, M; Bosia, M; Zanoletti, A; Fresi,
F; Buonocore, M; Cocchi, F; Guglielmino, C; Smeraldi,
E; Cavallaro, R. Theory of Mind intervention for outpatients with schizophrenia. Neuropsychol. Rehabil.: 2013;
23(3): 383-400 - Article
IF 2012: 2,011
P.88. Bedogni, F; Latib, A; De Marco, F; Agnifili, M; Oreglia, J;
Pizzocri, S; Latini, RA; Lanotte, S; Petronio, AS; De Carlo,
M; Ettori, F; Fiorina, C; Poli, A; Cirri, S; De Servi, S; Ramondo, A; Tarantini, G; Marzocchi, A; Fiorilli, R; Klugmann,
S; Ussia, GP; Tamburino, C; Maisano, F; Brambilla, N;
Colombo, A; Testa, L. Interplay between mitral regurgitation and transcatheter aortic valve replacement with the
corevalve revalving system: A multicenter registry. Circulation: 2013; 128(19): 2145-2153 - Article
IF 2012: 15,202
P.89. Bellebaum, C; Tettamanti, M; Marchetta, E; Della Rosa, P; Rizzo, G; Daum, I; Cappa, SF. Neural representations of unfamiliar objects are modulated by sensorimotor
experience. Cortex: 2013; 49(4): 1110-1125 - Article
IF 2012: 6,161
P.90. Belli, C; Cereda, S; Anand, S; Reni, M. Neoadjuvant
therapy in resectable pancreatic cancer: A critical review.
Cancer Treat. Rev.: 2013; 39(5): 518-524 - Review
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P.91. Bellodi, L; Martoni, RM; Galimberti, E; Cavallini, MC.
Low baseline startle in anorexia nervosa patients. Prog.
Neuropsychopharmacol. Biol. Psychiatry: 2013; 40: 2629 - Article
IF 2012: 3,552
P.92. Belloli, S; Brioschi, A; Politi, LS; Ronchetti, F; Calderoni, S; Raccagni, I; Pagani, A; Monterisi, C; Zenga, F; Zara, G; Fazio, F; Mauro, A; Moresco, RM. Characterization
of biological features of a rat F98 GBM model: A PET-MRI
study with [18F]FAZA and [18F]FDG. Nucl. Med. Biol.:
2013; 40(6): 831-840 - Article
IF 2012: 2,517
P.93. Bellone, M; Calcinotto, A. Ways to Enhance Lymphocyte Trafficking into Tumors and Fitness of Tumor Infiltrating
Lymphocytes. Front. Oncol.: 2013; 3: 231 - Review
IF 2012: No Impact Factor
P.94. Bellone, M; Calcinotto, A; Filipazzi, P; De Milito, A; Fais,
S; Rivoltini, L. The acidity of the tumor microenvironment is
a mechanism of immune escape that can be overcome by
proton pump inhibitors. OncoImmunology: 2013; 2(1):
e22058 - Article
IF 2012: No Impact Factor
P.95. Belloni, E; Panizza, P; Ravelli, S; De Cobelli, F; Gusmini, S; Losio, C; Sassi, I; Perseghin, G; Del Maschio, A.
MR-guided stereotactic breast biopsy using a mixed ferromagnetic-nonmagnetic coaxial system with 12- to 18gauge needles: clinical experience and long-term outcome. Radiol. Med.: 2013; 118(7): 1137-1149 - Article
IF 2012: 1,461
P.96. Beltrami, E; Valtorta, S; Moresco, R; Marcu, R; Belloli,
S; Fassina, A; Fazio, F; Pelicci, P; Giorgio, M. The p53p66Shc Apoptotic Pathway is Dispensable for Tumor Suppression whereas the p66Shc-generated Oxidative Stress
Initiates Tumorigenesis. Curr. Pharm. Des.: 2013; 19(15):
2708-2714 - Article
IF 2012: 3,311
P.97. Benedetti, F; Bollettini, I; Barberi, I; Radaelli, D; Poletti, S; Locatelli, C; Pirovano, A; Lorenzi, C; Falini, A; Colombo, C; Smeraldi, E. Lithium and GSK3-β promoter
gene variants influence white matter microstructure in bipolar disorder. Neuropsychopharmacology: 2013; 38(2):
313-327 - Article
IF 2012: 8,678
P.98. Benedetti, F; Giacosa, C; Radaelli, D; Poletti, S;
Pozzi, E; Dallaspezia, S; Falini, A; Smeraldi, E. Widespread changes of white matter microstructure in obsessive-compulsive disorder: Effect of drug status. Eur. Neuropsychopharmacol.: 2013; 23(7): 581-593 - Article
IF 2012: 4,595
P.99. Benedetti, F; Terman, M. Much Ado about... A moody
clock. Biol. Psychiatry: 2013; 74(4): 236-237 - Comment
P.100. Benedetti, S; Hoshiya, H; Tedesco, FS. Repair or replace? Exploiting novel gene and cell therapy strategies for
muscular dystrophies. FEBS J.: 2013; 280(17): 42634280 - Review
IF 2012: 4,250
P.101. Benham, AM; van Lith, M; Sitia, R; Braakman, I. Ero1PDI interactions, the response to redox flux and the implications for disulfide bond formation in the mammalian endoplasmic reticulum. Philos. Trans. R. Soc. B Biol. Sci.:
2013; 368(1617): 1-9 - Article
IF 2012: 6,230
P.102. Ben-Zvi, T; Hueber, PA; Abdollah, F; Liberman, D;
Bhojani, N; Gautam, G; Zorn, KC. Short term outcomes of
GreenLight vapor incision technique (VIT) of the prostate:
comparison of outcomes to standard GreenLight 120W
HPS vaporization in prostate volumes greater than 80 cc.
Can. J. Urol.: 2013; 20(1): 6633-6639 - Article
IF 2012: 0,740
P.103. Berini, J; Spica Russotto, V; Castelnuovo, P; Di Candia, S; Gargantini, L; Grugni, G; Iughetti, L; Nespoli, L;
Nosetti, L; Padoan, G; Pilotta, A; Trifiro, G; Chiumello, G;
Salvatoni, A; on behalf of the Genetic Obesity Study
Group of the Italian Society of Pediatric Endocrinology and
Diabetology (ISPED). Growth hormone therapy and respiratory disorders: Long-term follow-up in PWS children. J.
Clin. Endocrinol. Metab.: 2013; 98(9): E1516-E1523 - Article
IF 2012: 6,430
P.104. Berndt, SI; Gustafsson, S; Magi, R; Ganna, A; Wheeler,
E; Feitosa, MF; Justice, AE; Monda, KL; Croteau-Chonka,
DC; Day, FR; Esko, T; Fall, T; Ferreira, T; Gentilini, D; Jackson, AU; Luan, J; Randall, JC; Vedantam, S; Willer, CJ;
Winkler, TW; Wood, AR; Workalemahu, T; Hu, YJ; Lee,
SH; Li,ang, L; Li,n, DY; Min, JL; Neale, BM; Thorleifsson,
G; Yang, J; Albrecht, E; Amin, N; Bragg-Gresham, JL;
Cadby, G; Heijer, MD; Eklund, N; Fischer, K; Goel, A; Hottenga, JJ; Hu,ffman; JE; Jarick, I; Johansson, A; Johnson,
T; Kanoni, S; Kleber, ME; Konig, IR; Kristiansson, K; Kutalik, Z; Lamina, C; Lecoeur, C; Li, G; Mangino, M; McArdle,
WL; Medina-Gomez, C; Muller-Nurasyid, M; Ngwa, JS;
Nolte, IM; Paternoster, L; Pechlivanis, S; Perola, M; Peters,
MJ; Preuss, M; Rose, LM; Shi, J; Shungin, D; Smith, AV;
Strawbridge, RJ; Surakka, I; Teumer, A; Trip, MD; Tyrer, J;
Van Vliet-Ostaptchouk, JV; Vandenput, L; Waite, LL; Zhao,
JH; Absher, D; Asselbergs, FW; Atalay, M; Attwood, AP;
Balmforth, AJ; Basart, H; Beilby, J; Bonnycastle, LL; Brambilla, P; Bruinenberg, M; Campbell, H; Chasman, DI;
Chines, PS; Collins, FS; Connell, JM; O Cookson, W; De
Faire, U; De Vegt, F; Dei, M; Dimitriou, M; Edkins, S; Estrada, K; Evans, DM; Farrall, M; Ferrario, MM; Ferrieres, J;
Franke, L; Frau, F; Gejman, PV; Grallert, H; Gronberg, H;
Gudnason, V; Hall, AS; Hall, P; Hartikainen, AL; Hayward,
C; Heard-Costa, NL; Heath, AC; Hebebrand, J; Homuth,
G; Hu, FB; Hu,nt; SE; Hypponen, E; Iribarren, C; Jacobs,
KB; Jansson, JO; Jula, A; Kahonen, M; Kathiresan, S;
Kee, F; Khaw, KT; Kivimaki, M; Koenig, W; Kraja, AT; Kumari, M; Kuulasmaa, K; Kuusisto, J; Laitinen, JH; Lakka,
TA; Langenberg, C; Launer, LJ; Lind, L; Lindstrom, J; Liu,
J; Liuzzi, A; Lokki, ML; Lorentzon, M; Madden, PA; Magnusson, PK; Manunta, P; Marek, D; Marz, W; Leach, IM;
McKnight, B; Medland, SE; Mihailov, E; Milani, L; Montgomery, GW; Mooser, V; Muhleisen, TW; Munroe, PB;
Musk, AW; Narisu, N; Navis, G; Nicholson, G; Nohr, EA;
Ong, KK; Oostra, BA; Palmer, CN; Palotie, A; Peden, JF;
331
PUBLICATIONS
Pedersen, N; Peters, A; Polasek, O; Pouta, A; Pramstaller,
PP; Prokopenko, I; Putter, C; Radhakrishnan, A; Raitakari,
O; Rendon, A; Rivadeneira, F; Rudan, I; Saaristo, TE;
Sambrook, JG; Sanders, AR; Sanna, S; Saramies, J;
Schipf, S; Schreiber, S; Schunkert, H; Shi,n; SY; Signorini,
S; Sinisalo, J; Skrobek, B; Soranzo, N; Stancakova, A;
Stark, K; Stephens, JC; Stirrups, K; Stolk, RP; Stumvoll,
M; Swift, AJ; Theodoraki, EV; Thorand, B; Tregouet, DA;
Tremoli, E; Van Der Klauw, MM; Van Meurs, JB; Vermeulen, SH; Viikari, J; Virtamo, J; Vitart, V; Waeber, G;
Wang, Z; Widen, E; Wild, SH; Willemsen, G; Winkelmann,
BR; Witteman, JC; Wolffenbuttel, BH; Wong, A; Wright,
AF; Zillikens, MC; Amouyel, P; Boehm, BO; Boerwinkle, E;
Boomsma, DI; Caulfield, MJ; Chanock, SJ; Cupples, LA;
Cusi, D; Dedoussis, GV; Erdmann, J; Eriksson, JG;
Franks, PW; Froguel, P; Gieger, C; Gyllensten, U; Hamsten, A; Harris, TB; Hengstenberg, C; Hicks, AA; Hingorani, A; Hinney, A; Hofman, A; Hovingh, KG; Hveem, K; Illig, T; Jarvelin, MR; Jockel, KH; Keinanen-Kiukaanniemi,
SM; Kiemeney, LA; Kuh, D; Laakso, M; Lehtimaki, T;
Levinson, DF; Martin, NG; Metspalu, A; Morris, AD; Nieminen, MS; Njolstad, I; Ohlsson, C; Oldehinkel, AJ; Ouwehand, WH; Palmer, LJ; Penninx, B; Power, C; Province,
MA; Psaty, BM; Qi, L; Rauramaa, R; Ridker, PM; Ripatti, S;
Salomaa, V; Samani, NJ; Snieder, H; Sorensen, TI; Spector, TD; Stefansson, K; Tonjes, A; Tuomilehto, J; Uitterlinden, AG; Uusitupa, M; Van Der Harst, P; Vollenweider, P;
Wallaschofski, H; Wareham, NJ; Watkins, H; Wichmann,
HE; Wilson, JF; Abecasis, GR; Assimes, TL; Barroso, I;
Boehnke, M; Borecki, IB; Deloukas, P; Fox, CS; Frayling,
T; Groop, LC; Haritunian, T; Heid, IM; Hu,nter; D; Kaplan,
RC; Karpe, F; Moffatt, MF; Mohlke, KL; O’Connell, JR;
Pawitan, Y; Schadt, EE; Schlessinger, D; Steinthorsdottir,
V; Strachan, DP; Thorsteinsdottir, U; Van Duijn, CM; Visscher, PM; Di Blasio, AM; Hirschhorn, JN; Li,n,dgren; CM;
Morris, AP; Meyre, D; Scherag, A; McCarthy, MI; Speliotes, EK; North, KE; Loos, RJ; Ingelsson, E. Genomewide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.
Nature Genet.: 2013; 45(5): 501-512 - Article
IF 2012: 35,209
P.105. Bernelli, C; Ajello, S; Piraino, D; Chieffo, A; Montorfano, M; Maccagni, D; Durante, A; Sacco, FM; Margonato, A; Colombo, A. How should I treat a left main spontaneous dissection involving left anterior descending artery,
intermediate branch artery and left circumflex artery?. EuroIntervention: 2013; 9(2): 285-286+1-3 - Article
IF 2012: 3,173
P.106. Bernelli, C; Chieffo, A; Buchanan, GL; Montorfano,
M; Carlino, M; Latib, A; Figini, F; Takagi, K; Naganuma,
T; Maccagni, D; Colombo, A. New-generation drug-eluting stent experience in the percutaneous treatment of unprotected left main coronary artery disease: The NEST registry. J. Invasive Cardiol.: 2013; 25(6): 269-275 - Article
IF 2012: 1,569
P.107. Bernelli, C; Ferre, GF; Chieffo, A. Diabetes and
everolimus-eluting stents: What we know and what is still
missing. Insights from subanalysis of the SORT OUT IV trial. Exp. Rev. Cardiovasc. Ther.: 2013; 11(2): 151-154 Comment
IF 2012: No Impact Factor
P.108. Bernelli, C; Maisano, F; Chieffo, A; Montorfano, M;
Chan, J; Maccagni, D; Colombo, A. A new tool to manage side-branch occlusion after covered-stent implantation
for vascular complications: The neocarina reconstruction
technique. JACC Cardiovasc. Interventions: 2013; 6(8):
893-894 - Note
P.109. Berti, A; Campochiaro, C. Painful fingers. Eur. J. Intern. Med.: 2013; 24(6): e63-e64 - Images
P.110. Bertilaccio, MTS; Scielzo, C; Simonetti, G; Ten
Hacken, E; Apollonio, B; Ghia, P; Caligaris-Cappio, F.
Xenograft models of chronic lymphocytic leukemia: Prob-
lems, pitfalls and future directions. Leukemia: 2013; 27(3):
534-540 - Review
IF 2012: 10,164
P.111. Bertino, P; Panigada, M; Soprana, E; Bianchi, V;
Bertilaccio, S; Sanvito, F; Rose, AH; Yang, H; Gaudino,
G; Hoffmann, PR; Siccardi, A; Carbone, M. Fowlpoxbased survivin vaccination for malignant mesothelioma
therapy. Int. J. Cancer: 2013; 133(3): 612-623 - Article
IF 2012: 6,198
P.112. Bertoglio, L; Melissano, G; Civilini, E; Chiesa, R.
Stent misalignment of the Zenith Dissection Endovascular
System. J. Vasc. Surg.: 2013; 57(2): 515-517 - Article
IF 2012: 2,879
P.113. Bertoldi, L; Latib, A; Piraino, D; Regazzoli, D; Sticchi, A; Pizzetti, G; Camici, PG; Colombo, A. Renal denervation in a patient with two renal accessory arteries: A
case report. Blood Pressure: 2013; 22(5): 325-328 - Article
IF 2012: 1,391
P.114. Bertolotti, M and Bestetti, S and Garcia-Manteiga,
JM and Medraño-Fernandez, I; Dal Mas, A; Malosio,
ML; Sitia, R. Tyrosine kinase signal modulation: a matter
of H2O2 membrane permeability?. Antioxid. Redox Signal.: 2013; 19(13): 1447-1451 - Review
IF 2012: 7,189
P.115. Bettin, P; Di Matteo, F. Glaucoma: Present challenges
and future trends. Ophthalmic Res.: 2013; 50(4): 197-208
- Review
IF 2012: 1,562
P.116. Bianchi, AM; Marchetta, E; Tana, MG; Tettamanti, M;
Rizzo, G. Frequency-based approach to the study of semantic brain networks connectivity. J. Neurosci. Methods:
2013; 212(2): 181-189 - Article
IF 2012: 2,114
P.117. Bianchi, E; Molteni, R; Pardi, R; Dubini, G. Microfluidics for in vitro biomimetic shear stress-dependent leukocyte adhesion assays. J. Biomech.: 2013; 46(2): 276-283
- Review
IF 2012: 2,716
P.118. Bianchi, M and Becker, A; Abdollah, F; Trinh, QD;
Hansen, J; Tian, Z; Shariat, SF; Perrotte, P; Karakiewicz,
PI; Sun, M. Rates of open versus laparoscopic and partial
versus radical nephrectomy for T1a renal cell carcinoma: A
population-based evaluation. Int. J. Urol.: 2013; 20(11):
1064-1071 - Article
IF 2012: 1,734
P.119. Bianchi, M and Becker, A; Hansen, J; Trinh, QD; Tian,
Z; Abdollah, F; Briganti, A; Shariat, SF; Perrotte, P; Montorsi, F; Karakiewicz, PI; Sun, M. Conditional survival after
nephrectomy for renal cell carcinoma (RCC): Changes in
future survival probability over time. BJU Int.: 2013; 111(8):
E283-E289 - Article
IF 2012: 3,046
P.120. Bianchi, M and Becker, A; Trinh, QD; Abdollah, F;
Tian, Z; Shariat, SF; Montorsi, F; Perrotte, P; Graefen, M;
Karakiewicz, PI; Sun, M. An analysis of patients with T2 renal cell carcinoma (RCC) according to tumour size: A population-based analysis. BJU Int.: 2013; 111(8): 1184-1190
- Article
IF 2012: 3,046
P.121. Bianchini, G; Gianni, L. An unmet need: tailoring extended adjuvant endocrine therapy. Br. J. Cancer: 2013;
109(12): 2951-2953 - Comment
P.122. Bianchini, G; Gianni, L. HER2-directed T-cell receptor-mimicking antibody: A me too or an example of novel
antitumor aggressive mimicry?. J. Natl. Cancer Inst.: 2013;
105(3): 161-163 - Comment
P.123. Bianchini, G; Pusztai, L; Karn, T; Iwamoto, T; Rody, A;
Kelly, CM; Müller, V; Schmidt, M; Qi, Y; Holtrich, U; Becker,
S; Santarpia, L; Fasolo, A; Del Conte, G; Zambetti, M;
Sotiriou, C; Haibe-Kains, B; Symmans, WF; Gianni, L.
Proliferation and estrogen signaling can distinguish patients
PUBLICATIONS
at risk for early versus late relapse among estrogen receptor positive breast cancers. Breast Cancer Res.: 2013; 15:
R86 - Article
IF 2012: 5,872
P.124. Biffi, A and Montini, E; Lorioli, L; Cesani, M; Fumagalli, F; Plati, T; Baldoli, C; Martino, S; Calabria, A;
Canale, S; Benedicenti, F; Vallanti, G; Biasco, L; Leo, S;
Kabbara, N; Zanetti, G; Rizzo, WB; Mehta, NA; Cicalese,
MP; Casiraghi, M; Boelens, JJ; Del Carro, U; Dow, DJ;
Schmidt, M; Assanelli, A; Neduva, V; Di Serio, C; Stupka, E; Gardner, J; von Kalle, C; Bordignon, C; Ciceri, F;
Rovelli, A; Roncarolo, MG; Aiuti, A; Sessa, M; Naldini,
L. Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy. Science: 2013;
341(6148): 1233158 - Article
IF 2012: 31,027
P.125. Biffi, E and Regalia, G; Menegon, A; Ferrigno, G; Pedrocchi, A. The influence of neuronal density and maturation on network activity of hippocampal cell cultures: a
methodological study. PLoS One: 2013; 8(12): e83899 Article
IF 2012: 3,730
P.126. Biglioli, F; Mortini, P; Pedrazzoli, M; D’Alessandro, L;
Bardazzi, A; Colletti, G. The reconstruction of the sphenoorbital region using latissimus dorsi flap and costal graft. J.
Craniofac. Surg.: 2013; 24(4): e379-e383 - Article
IF 2012: 0,686
P.127. Bignami, E; Casamassima, N; Frati, E; Lanzani, C;
Corno, L; Alfieri, O; Gottlieb, S; Simonini, M; Shah, KB;
Mizzi, A; Messaggio, E; Zangrillo, A; Ferrandi, M; Ferrari,
P; Bianchi, G; Hamlyn, JM; Manunta, P. Preoperative endogenous ouabain predicts acute kidney injury in cardiac
surgery patients. Crit. Care Med.: 2013; 41(3): 744-755 Article
IF 2012: 6,124
P.128. Bignami, E; Greco, T; Barile, L; Silvetti, S; Nicolotti,
D; Fochi, O; Cama, E; Costagliola, R; Landoni, G; Biondi-Zoccai, G; Zangrillo, A. The effect of isoflurane on survival and myocardial infarction: A meta-analysis of randomized controlled studies. J. Cardiothorac. Vasc. Anesth.:
2013; 27(1): 50-58 - Article
IF 2012: 1,448
P.129. Biino, G; Santimone, I; Minelli, C; Sorice, R; Frongia, B;
Traglia, M; Ulivi, S; Di Castelnuovo, A; Gogele, M; Nutile,
T; Francavilla, M; Sala, C; Pirastu, N; Cerletti, C; Iacoviello,
L; Gasparini, P; Toniolo, D; Ciullo, M; Pramstaller, P; Pirastu, M; de Gaetano, G; Balduini, CL. Age- And Sex-Related Variations in Platelet Count in Italy: A Proposal of Reference Ranges Based on 40987 Subjects’ Data. PLoS
ONE: 2013; 8(1): e54289 - Article
IF 2012: 3,730
P.130. Bjerk, SM; Baker, JV; Emery, S; Neuhaus, J; Angus, B;
Gordin, FM; Pett, SL; Stephan, C; Kunisaki, KM; for the
INSIGHT SMART Study Group. Biomarkers and bacterial pneumonia risk in patients with treated HIV infection: a
case-control study. PLoS One: 2013; 8(2): e56249 - Article
IF 2012: 3,730
P.131. Boari, N; Gagliardi, F; Spina, A; Bailo, M; Franzin, A;
Mortini, P. Management of spheno-orbital en plaque
meningiomas: clinical outcome in a consecutive series of
40 patients. Br. J. Neurosurg.: 2013; 27(1): 84-90 - Article
IF 2012: 0,858
P.132. Bocci, T; Moretto, C; Tognazzi, S; Briscese, L; Naraci,
M; Leocani, L; Mosca, F; Ferrari, M; Sartucci, F. How does a surgeon’s brain buzz? An EEG coherence study on
the interaction between humans and robot. Behav. Brain
Funct.: 2013; 9: 14 - Article
IF 2012: 2,789
P.133. Boi, M; Rinaldi, A; Kwee, I; Bonetti, P; Todaro, M; Tabbò, F; Piva, R; Rancoita, PM; Matolcsy, A; Timar, B; Tousseyn, T; Rodríguez-Pinilla, SM; Piris, MA; Beà, S; Campo,
E; Bhagat, G; Swerdlow, SH; Rosenwald, A; Ponzoni, M;
Young, KH; Piccaluga, PP; Dummer, R; Pileri, S; Zucca, E;
Inghirami, G; Bertoni, F. PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma. Blood:
2013; 122(15): 2683-2693 - Article
IF 2012: 9,060
P.134. Bolamperti, S; Mrak, E; Moro, G; Sirtori, P; Fraschini, G; Guidobono, F; Rubinacci, A; Villa, I. 17β-Estradiol
positively modulates growth hormone signaling through the
reduction of SOCS2 negative feedback in human osteoblasts. Bone: 2013; 55(1): 84-92 - Article
IF 2012: 3,823
P.135. Bolli, R; Tang, XL; Sanganalmath, SK; Rimoldi, O;
Mosna, F; Abdel-Latif, A; Jneid, H; Rota, M; Leri, A; Kajstura, J. Intracoronary delivery of autologous cardiac stem
cells improves cardiac function in a porcine model of
chronic ischemic cardiomyopathy. Circulation: 2013;
128(2): 122-131 - Article
IF 2012: 15,202
P.136. Bombardini, T; Zoppè, M; Ciampi, Q; Cortigiani, L;
Agricola, E; Salvadori, S; Loni, T; Pratali, L; Picano, E. Myocardial contractility in the stress echo lab: from pathophysiological toy to clinical tool. Cardiovasc. Ultrasound:
2013; 11: 41 - Review
IF 2012: 1,320
P.137. Bombelli, S; Zipeto, MA and Torsello, B; Bovo, G; Di
Stefano, V; Bugarin, C; Zordan, P; Viganò, P; Cattoretti,
G; Strada, G; Bianchi, C; Perego, RA. PKHhigh cells within clonal human nephrospheres provide a purified adult renal stem cell population. Stem Cell Research: 2013; 11(3):
1163-1177 - Article
IF 2012: 4,467
P.138. Bondi, S; Giordano, L; Limardo, P; Bussi, M. Role of
Montgomery salivary stent placement during pharyngolaryngectomy, to prevent pharyngocutaneous fistula in highrisk patients. J. Laryngol. Otol.: 2013; 127(1): 54-57 - Article
IF 2012: 0,681
P.139. Bondi, S; Limardo, P; Toma, S; Bussi, M. Nonvestibular head and neck schwannomas: a 10-year experience. Eur. Arch. Oto-Rhino-Laryngol.: 2013; 270(8):
2365-2369 - Article
IF 2012: 1,458
P.140. Bonetti, P and Testoni, M; Scandurra, M; Ponzoni, M;
Piva, R; Mensah, AA; Rinaldi, A; Kwee, I; Tibiletti, MG;
Iqbal, J; Greiner, TC; Chan, WC; Gaidano, G; Piris, MA;
Cavalli, F; Zucca, E; Inghirami, G; Bertoni, F. Deregulation
of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma. Blood: 2013; 122(13): 22332241 - Article
IF 2012: 9,060
P.141. Bonini, C; Mondino, A. Trick to treat: tricking the thymus to treat cancer. Blood: 2013; 122(3): 304-306 Comment
P.142. Bonomi, S; Di Matteo, A; Buratti, E; Cabianca, DS;
Baralle, FE; Ghigna, C; Biamonti, G. HnRNP A1 controls a
splicing regulatory circuit promoting mesenchymal-to-epithelial transition. Nucleic Acids Res.: 2013; 41(18): 86658679 - Article
IF 2012: 8,278
P.143. Bonomini, M; Di Liberato, L; Del Rosso, G; Stingone, A;
Marinangeli, G; Consoli, A; Bertoli, S; De Vecchi, A; Bosi,
E; Russo, R; Corciulo, R; Gesualdo, L; Giorgino, F; Cerasoli, P; Di Castelnuovo, A; Monaco, MP; Shockley, T;
Rossi, C; Arduini, A. Effect of an l-Carnitine-Containing
Peritoneal Dialysate on Insulin Sensitivity in Patients Treated
With CAPD: A 4-Month, Prospective, Multicenter Randomized Trial. Am. J. Kidney Dis.: 2013; 62(5): 929-938 Article
IF 2012: 5,294
P.144. Borges, AH; Silverberg, MJ; Wentworth, D; Grulich, AE;
Fatkenheuer, G; Mitsuyasu, R; Tambussi, G; Sabin, CA;
333
PUBLICATIONS
Neaton, JD; Lundgren, JD; for the INSIGHT SMART, ESPRIT, SILCAAT Study Groups. Predicting risk of cancer
during HIV infection: The role of inflammatory and coagulation biomarkers. AIDS: 2013; 27(9): 1433-1441 - Article
IF 2012: 6,407
P.145. Borggren, M; Vinner, L; Skovgaard Andresen, B;
Grevstad, B; Repits, J; Melchers, M;Elvang, TL; Sanders,
RW; Martinon, F; Dereuddre-Bosquet, N; Bowles, EJ;
Stewart-Jones, G; Biswas, P; Scarlatti, G; Jansson, M;
Heyndrickx, L; Le Grand, R; Fomsgaard, A. Optimization of
HIV-1 Envelope DNA Vaccine Candidates within Three Different Animal Models, Guinea Pigs, Rabbits and Cynomolgus Macaques. Vaccines: 2013; 1(3): 305-327 - Article
IF 2012: No Impact Factor
P.146. Boschi, F; Pagliazzi, M; Rossi, B; Cecchini, MP; Gorgoni, G; Salgarello, M; Spinelli, AE. Small-animal radionuclide luminescence imaging of thyroid and salivary glands
with Tc99m-pertechnetate. J. Biomed. Opt.: 2013; 18(7):
76005 - Article
IF 2012: 2,881
P.147. Bose, F; Petti, L; Diani, M; Moscheni, C; Molteni, S; Altomare, A; Rossi, RL; Talarico, D; Fontana, R; Russo, V;
Altomare, G; Reali, E. Inhibition of CCR7/CCL19 axis in lesional skin is a critical event for clinical remission induced
by TNF blockade in patients with psoriasis. Am. J. Pathol.:
2013; 183(2): 413-421 - Article
IF 2012: 4,522
P.148. Bosetti, M; Bianchi, AE; Zaffe, D; Cannas, M. Comparative in vitro study of four commercial biomaterials used
for bone grafting. J. Appl. Biomater. Funda. Mater.: 2013;
11(2): 80-88 - Article
IF 2012: Indexed by JCR
P.149. Bosi, E; Bax, G; Scionti, L; Spallone, V; Tesfaye, S;
Valensi, P; Ziegler, D; on behalf of the FREMS European
Trial Study Group. Frequency-modulated electromagnetic
neural stimulation (FREMS) as a treatment for symptomatic
diabetic neuropathy: results from a double-blind, randomised, multicentre, long-term, placebo-controlled clinical trial. Diabetologia: 2013; 56(3): 467-475 - Article
IF 2012: 6,487
P.150. Bosi, E; Scavini, M; Ceriello, A; Cucinotta, D; Tiengo,
A; Marino, R; Bonizzoni, E; Giorgino, F; on behalf of the
PRISMA STUDY GROUP. Intensive structured self-monitoring of blood glucose and glycemic control in noninsulintreated type 2 diabetes: the PRISMA randomized trial. Diabetes Care: 2013; 36(10): 2887-2894 - Article
IF 2012: 7,735
P.151. Bosiers, M; Deloose, K; Callaert, J; Maene, L; Beelen,
R; Keirse, K; Verbist, J; Peeters, P; Schroe, H; Lauwers,
G; Lansink, W; Vanslembroeck, K; D’Archambeau, O;
Hendriks, J; Lauwers, P; Vermassen, F; Randon, C; Van
Herzeele, I; De Ryck, F; De Letter, J; Lanckneus, M; Van
Betsbrugge, M; Thomas, B; Deleersnijder, R; Vandekerkhof, J; Baeyens, I; Berghmans, T; Buttiens, J; Van Den
Brande, P; Debing, E; Rabbia, C; Ruffino, A; Tealdi, D;
Nano, G; Stegher, S; Gasparini, D; Piccoli, G; Coppi, G;
Silingardi, R; Cataldi, V; Paroni, G; Palazzo, V; Stella, A;
Gargiulo, M; Muccini, N; Nessi, F; Ferrero, E; Pratesi, C;
Fargion, A; Chiesa, R; Marone, E; Bertoglio, L; Cremonesi, A; Dozza, L; Galzerano, G; De Donato, G; Setacci, C. BRAVISSIMO: 12-month results from a large scale
prospective trial. J. Cardiovasc. Surg.: 2013; 54(2): 235253 - Article
IF 2012: 1,510
P.152. Bossi, A; Briganti, A. AUA-ASTRO guidelines for postRP radiation fail to go nuclear. Nat. Rev. Urol.: 2013; 10(9):
498-499 - Article
IF 2012: 4,793
P.153. Bosutti, A; Qi, J; Pennucci, R; Bolton, D; Matou, S; Ali,
K; Tsai, LH; Krupinski, J; Petcu, EB; Montaner, J; Al
Baradie, R; Caccuri, F; Caruso, A; Alessandri, G; Kumar,
S; Rodriguez, C; Martinez-Gonzalez, J; Slevin, M. Target-
ing p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia. PLoS ONE: 2013; 8(9): e75538 - Article
IF 2012: 3,730
P.154. Boto-De-Los-Bueis, A; Benitez Del Castillo, JM; Alen
Cordero, RL; Godia, R; Alvarez, G; Rama, P. “salt and
Pepper” Corneal Endothelium. Ophthalmology: 2013;
120(3): 648-649.e1 - Letter
P.155. Bozzali, M; Parker, GJM; Spano, B; Serra, L; Giulietti,
G; Perri, R; Magnani, G; Marra, C; Vita, MG; Caltagirone,
C; Cercignani, M. Brain tissue modifications induced by
cholinergic therapy in Alzheimer’s disease. Hum. Brain
Mapp.: 2013; 34(12): 3158-3167 - Article
IF 2012: 6,878
P.156. Bozzali, M; Spano, B; Parker, GJM; Giulietti, G; Castelli, M; Basile, B; Rossi, S; Serra, L; Magnani, G; Nocentini,
U; Caltagirone, C; Centonze, D; Cercignani, M. Anatomical brain connectivity can assess cognitive dysfunction in
multiple sclerosis. Mult. Scler.: 2013; 19(9): 1161-1168 Article
IF 2012: 4,472
P.157. Bozzini, G; Picozzi, S; Gadda, F; Colombo, R; Decobelli, O; Palou, J; Colpi, G; Carmignani, L. Long-term follow-up using testicle-sparing surgery for Leydig cell tumor.
Clin. Genitourin. Cancer: 2013; 11(3): 321-324 - Article
IF 2012: 1,429
P.158. Bozzolo, EP; Ramirez, GA; Bonavida, G; Lanzani,
C; Scotti, R; Dell’Antonio, G; Baldissera, E; Canti, V;
Manfredi, AA; Rovere-Querini, P; Sabbadini, MG. Efficacy and toxicity of treatments for nephritis in a series of
consecutive lupus patients. Autoimmunity: 2013; 46(8):
537-546 - Article
IF 2012: 2,767
P.159. Brauer, J; Anwander, A; Perani, D; Friederici, AD. Dorsal and ventral pathways in language development. Brain
Lang.: 2013; 127(2): 289-295 - Article
IF 2012: 3,386
P.160. Bravatà, V; Stefano, A; Cammarata, FP; Minafra, L;
Russo, G; Nicolosi, S; Pulizzi, S; Gelfi, C; Gilardi, MC;
Messa, C. Genotyping analysis and 18FDG uptake in
breast cancer patients: A preliminary research. J. Exp.
Clin. Cancer Res.: 2013; 32: 23 - Article
IF 2012: 3,066
P.161. Briganti, A; Bianchi, M; Sun, M; Suardi, N; Gallina,
A; Abdollah, F; Bertini, R; Colombo, R; Di Girolamo, V;
Salonia, A; Scattoni, V; Karakiewicz, PI; Guazzoni, G;
Rigatti, P; Montorsi, F. Impact of the introduction of a robotic training programme on prostate cancer stage migration at a single tertiary referral centre. BJU Int.: 2013;
111(8): 1222-1230 - Article
IF 2012: 3,046
P.162. Briganti, A; Joniau, S; Gandaglia, G; Cozzarini, C;
Sun, M; Tombal, B; Haustermans, K; Hinkelbein, W; Shariat, SF; Karakiewicz, PI; Montorsi, F; Van Poppel, H;
Wiegel, T. Patterns and predictors of early biochemical recurrence after radical prostatectomy and adjuvant radiation
therapy in men with pT3N0 prostate cancer: implications
for multimodal therapies. Int. J. Radiat. Oncol. Biol. Phys.:
2013; 87(5): 960-967 - Article
IF 2012: 4,524
P.163. Briganti, A; Spahn, M; Joniau, S; Gontero, P; Bianchi,
M; Kneitz, B; Chun, FK; Sun, M; Graefen, M; Abdollah, F;
Marchioro, G; Frohenberg, D; Giona, S; Frea, B;
Karakiewicz, PI; Montorsi, F; Van Poppel, H; Jeffrey
Karnes, R; on behalf of the European Multicenter Prostate
Cancer Clinical and Translational Research Group (EMPaCT). Impact of Age and Comorbidities on Long-term
Survival of Patients with High-risk Prostate Cancer Treated
with Radical Prostatectomy: A Multi-institutional Competing-risks Analysis. Eur. Urol.: 2013; 63(4): 693-701 - Article
IF 2012: 10,476
PUBLICATIONS
P.164. Briganti, A; Suardi, N; Gallina, A; Abdollah, F; Montorsi, F. Pelvic Lymph Node Dissection in Prostate Cancer:
The Mystery Is Taking Shape. Eur. Urol.: 2013; 63(3): 459461 - Comment
P.165. Brilli, E and Reitano, E and Conti, L; Conforti, P and
Gulino; R; Consalez, GG; Cesana, E; Smith, A; Rossi, F;
Cattaneo, E. Neural stem cells engrafted in the adult brain
fuse with endogenous neurons. Stem Cells Dev.: 2013;
22(4): 538-547 - Article
IF 2012: 4,670
P.166. Broccoli, V; Caiazzo, M. Nuclear receptors: Oxysterols detour to neurodevelopment. Nat. Chem. Biol.:
2013; 9(2): 70-71 - Comment
P.167. Broccolo, F; Drago, F; Cassina, G; Fava, A; Fusetti, L;
Matteoli, B; Ceccherini-Nelli, L; Sabbadini, MG; Lusso, P;
Parodi, A; Malnati, MS. Selective reactivation of human
herpesvirus 6 in patients with autoimmune connective tissue diseases. J. Med. Virol.: 2013; 85(11): 1925-1934 Article
IF 2012: 2,373
P.168. Broccolo, F; Fusetti, L; Rosini, S; Caraceni, D; Zappacosta, R; Ciccocioppo, L; Matteoli, B; Halfon, P; Malnati,
MS; Ceccherini-Nelli, L. Comparison of oncogenic HPV
type-specific viral DNA load and E6/E7 mRNA detection in
cervical samples: Results from a multicenter study. J. Med.
Virol.: 2013; 85(3): 472-482 - Article
IF 2012: 2,373
P.169. Broccolo, F; Lusso, P; Malnati, M. Calibration technologies for correct determination of Epstein-Barr virus, human herpesvirus 6 (HHV-6), and HHV-8 antiviral drug susceptibilities by use of real-time-PCR-based assays. J. Clin.
Microbiol.: 2013; 51(6): 2013 - Letter
P.170. Broggi, S; Cantone, MC; Chiara, A; Di Muzio, N;
Longobardi, B; Mangili, P; Veronese, I. Application of failure mode and effects analysis (FMEA) to pretreatment
phases in tomotherapy. J. Appl. Clin. Med. Phys: 2013;
14(5): 265-277 - Article
IF 2012: 0,959
P.171. Brombin, C; Diomede, L; Tudor, D; Drillet, AS; Pastori, C; Poli, E; Riva, A; Uberti-Foppa, C; Galli, M; Di
Serio, C; Bomsel, M; Lopalco, L. A Nonparametric Procedure for Defining a New Humoral Immunologic Profile in
a Pilot Study on HIV Infected Patients. PLoS ONE: 2013;
8(3): e58768 - Article
IF 2012: 3,730
P.172. Brookman-May, SD and May, M; Shariat, SF; Novara,
G; Zigeuner, R; Cindolo, L; De Cobelli, O; De Nunzio, C;
Pahernik, S; Wirth, MP; Longo, N; Simonato, A; Serni, S;
Siracusano, S; Volpe, A; Morgia, G; Bertini, R; Dalpiaz, O;
Stief, C; Ficarra, V; Members of the CORONA-Project,
the SATURN-Project; and the Young Academic Urologists
Renal Cancer Group. Time to recurrence is a significant
predictor of cancer-specific survival after recurrence in patients with recurrent renal cell carcinoma - Results from a
comprehensive multi-centre database (CORONA/SATURN-Project). BJU Int.: 2013; 112(7): 909-916 - Article
IF 2012: 3,046
P.173. Brunetto, E and Ferrara, AM; Rampoldi, F; Talarico,
A; Dal Cin, E; Grassini, G; Spagnuolo, L; Sassi, I; Ferro,
A; Veronica Cuorvo, L; Barbareschi, M; Piccinin, S; Maestro, R; Pecciarini, L; Doglioni, C; Cangi, MG. CDC25A
protein stability represents a previously unrecognized target of HER2 signaling in human breast cancer: Implication
for a potential clinical relevance in trastuzumab treatment.
Neoplasia: 2013; 15(6): 579-590 - Article
IF 2012: 5,470
P.174. Bruschi, GB; Crespi, R; Capparè, P; Bravi, F; Bruschi,
E; Gherlone, E. Localized Management of Sinus Floor
Technique for Implant Placement in Fresh Molar Sockets.
Clin. Implant. Dent. Relat. Res.: 2013; 15(2): 243-250 Article
IF 2012: 3,821
P.175. Buchanan, GL; Chieffo, A; Bernelli, C; Montorfano,
M; Carlino, M; Latib, A; Figini, F; Giannini, F; Durante,
A; Ielasi, A; Castelli, A; Colombo, A. Two-year outcomes
following unprotected left main stenting with first vs. newgeneration drug-eluting stents: the FINE registry. EuroIntervention: 2013; 9(7): 809-816 - Article
IF 2012: 3,173
P.176. Buchanan, GL; Chieffo, A; Montorfano, M;
Maccagni, D; Maisano, F; Latib, A; Covello, RD;
Grimaldi, A; Alfieri, O; Colombo, A. A “modified
crossover technique” for vascular access management in
high-risk patients undergoing transfemoral transcatheter
aortic valve implantation. Catheter. Cardiovasc. Interv.:
2013; 81(4): 579-583 - Article
IF 2012: 2,514
P.177. Budhiraja, S and Famiglietti, M; Bosque, A; Planelles,
V; Rice, AP. Cyclin T1 and CDK9 T-loop phosphorylation
are downregulated during establishment of HIV-1 latency in
primary resting memory CD4+ T cells. J. Virol.: 2013;
87(2): 1211-1220 - Article
IF 2012: 5,076
P.178. Buja, P and Napodano, M; Tamburino, C; Petronio, AS;
Ettori, F; Santoro, G; Ussia, GP; Klugmann, S; Bedogni, F;
Ramondo, A; Maisano, F; Marzocchi, A; Poli, A; Gasparetto, V; Antoniucci, D; Colombo, A; Tarantini, G; on behalf of the Italian Multicenter CoreValve Registry Investigators. Comparison of variables in men versus women undergoing transcatheter aortic valve implantation for severe
aortic stenosis (from Italian Multicenter CoreValve Registry).
Am. J. Cardiol.: 2013; 111(1): 88-93 - Article
IF 2012: 3,209
P.179. Burgoyne, T; Jolly, R; Martin-Martin, B; Seabra, MC;
Piccirillo, R; Schiaffino, MV; Futter, CE. Expression of
OA1 limits the fusion of a subset of MVBs with lysosomes a mechanism potentially involved in the initial biogenesis of
melanosomes. J. Cell Sci.: 2013; 126(Pt 22): 5143-5152
- Article
IF 2012: 5,877
P.180. Burioni, R; Lang, AB; Capra, JD. Human monoclonal
antibodies as a new class of antiinfective compounds.
Clin. Dev. Immunol.: 2013; 2013: 297120 - Comment
P.181. Bussi, M; Palonta, F; Toma, S. Grafting in revision rhinoplasty [Gli innesti nella rinoplastica di revisione]. Acta
Otorhinolaryngol. Ital.: 2013; 33(3): 183-189 - Article
IF 2012: 0,786
P.182. Butera, C; Guerriero, R; Amadio, S; Ungaro, D;
Tesfaghebriel, H; Bianchi, F; Comi, G; Del Carro, U.
Functional end-plate recovery in long-term botulinum toxin
therapy of hemifacial spasm: a nerve conduction study.
Neurol. Sci.: 2013; 34(2): 209-215 - Article
IF 2012: 1,412
P.183. Buzzatti, N; Maisano, F; Latib, A; Cioni, M; Taramasso, M; Mussardo, M; Colombo, A; Alfieri, O. Computed tomography-based evaluation of aortic annulus,
prosthesis size and impact on early residual aortic regurgitation after transcatheter aortic valve implantation. Eur. J.
Cardiothorac. Surg.: 2013; 43(1): 43-51 - Article
IF 2012: 2,674
P.184. Cabrini, L; Nobile, L; Cama, E; Borghi, G; Pieri, M;
Bocchino, S; Zangrillo, A. Non-invasive ventilation during
upper endoscopies in adult patients. A systematic review.
Minerva Anestesiol.: 2013; 79(6): 683-694 - Review
IF 2012: 2,818
P.185. Caffarra, P; Gardini, S; Cappa, S; Dieci, F; Concari, L;
Barocco, F; Ghetti, C; Ruffini, L; Prati, GD. Degenerative
jargon aphasia: Unusual progression of logopenic/phonological progressive aphasia?. Behav. Neurol.: 2013; 26(1):
89-93 - Article
IF 2012: 1,247
P.186. Caganova, M; Carrisi, C and Varano, G; Mainoldi, F;
Zanardi, F; Germain, PL; George, L; Alberghini, F; Ferrarini,
L; Talukder, AK; Ponzoni, M; Testa, G; Nojima, T;
335
PUBLICATIONS
Doglioni, C; Kitamura, D; Toellner, KM; Su, IH; Casola, S.
Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J Clin Invest:
2013; 123(12): 5009-5022 - Article
IF 2012: 12,812
P.187. Cahn, P; Pozniak, AL; Mingrone, H; Shuldyakov, A;
Brites, C; Andrade-Villanueva, JF; Richmond, G; Buendia,
CB; Fourie, J; Ramgopal, M; Hagins, D; Felizarta, F;
Madruga, J; Reuter, T; Newman, T; Small, CB; Lombaard,
J; Grinsztejn, B; Dorey, D; Underwood, M; Griffith, S; Min,
S; on behalf of the extended SAILING Study Team.
Dolutegravir versus raltegravir in antiretroviral-experienced,
integrase-inhibitor-naive adults with HIV: week 48 results
from the randomised, double-blind, non-inferiority SAILING
study. Lancet: 2013; 382(9893): 700-708 - Article
IF 2012: 39,060
P.188. Caiulo, VA; Gargani, L; Caiulo, S; Fisicaro, A; Moramarco, F; Latini, G; Picano, E; Mele, G. Lung ultrasound
characteristics of community-acquired pneumonia in hospitalized children. Pediatr. Pulmonol.: 2013; 48(3): 280287 - Article
IF 2012: 2,375
P.189. Calandrino, R; Ardu, V; Corletto, D; Del Vecchio, A;
Origgi, D; Signorotto, P; Spinelli, A; Tosi, G; Bolognesi,
A; Cariati, M; Kluzer, A; Muscarella, S. Evaluation of second cancer induction risk by CT follow-up in oncological
long-surviving patients. Health Phys.: 2013; 104(1): 1-8 Article
IF 2012: 1,017
P.190. Calcagno, A; Nozza, S; Gonzalez de Requena, D;
Galli, A; D’Avolio, A; Simiele, M; Chiappetta, S; Di Perri,
G; Lazzarin, A; Bonora, S. Pharmacokinetics of maraviroc
administered at 150 mg once daily in association with
lopinavir/ritonavir in HIV-positive treatment-naive patients.
J. Antimicrob. Chemother.: 2013; 68(7): 1686-1688 - Letter
IF 2012: 5,338
P.191. Calderini, A; Pantaleo, G; Rossi, A; Gazzolo, D;
Polizzi, E. Adjunctive effect of chlorhexidine antiseptics in
mechanical periodontal treatment: First results of a preliminary case series. Int. J. Dent. Hyg.: 2013; 11(3): 180-185
- Article
IF 2012: 0,802
P.192. Callea, M; Teggi, R; Yavuz, I; Tadini, G; Priolo, M; Crovella, S; Clarich, G; Grasso, DL. Ear nose throat manifestations in hypoidrotic ectodermal dysplasia. Int. J. Pediatr.
Otorhinolaryngol.: 2013; 77(11): 1801-1804 - Review
IF 2012: 1,350
P.193. Camaschella, C. How I manage patients with atypical
microcytic anaemia. Br. J. Haematol.: 2013; 160(1): 12-24
- Review
IF 2012: 4,942
P.194. Camaschella, C. Treating iron overload. New Engl. J.
Med.: 2013; 368(24): 2325-2327 - Article
IF 2012: 51,658
P.195. Camaschella, C. Iron and hepcidin: a story of recycling
and balance. Hematology Am. Soc. Hematol. Educ. Program: 2013; 2013: 1-8 - Conference Paper
IF 2012: No Impact Factor
P.196. Cambiaghi, M and Cursi, M and Magri, L; Castoldi,
V; Comi, G; Minicucci, F; Galli, R; Leocani, L. Behavioural and EEG effects of chronic rapamycin treatment in a
mouse model of Tuberous Sclerosis Complex. Neuropharmacology: 2013; 67: 1-7 - Article
IF 2012: 4,114
P.197. Cambiaghi, M and Cursi, M; Monzani, E; Benfenati,
F; Comi, G; Minicucci, F; Valtorta, F; Leocani, L. Temporal evolution of neurophysiological and behavioral features of synapsin I/II/III triple knock-out mice. Epilepsy
Res.: 2013; 103(2/3): 153-160 - Article
IF 2012: 2,241
P.198. Campanella, A; Santambrogio, P; Fontana, F; Frenquelli, M; Cenci, S; Marcatti, M; Sitia, R; Tonon, G; Camaschella, C. Iron increases the susceptibility of multiple
myeloma cells to bortezomib. Haematologica: 2013;
98(6): 971-979 - Article
IF 2012: 5,935
P.199. Canducci, F; Ceresola, ER; Saita, D; Castagna, A;
Gianotti, N; Underwood, M; Burioni, R; Lazzarin, A;
Clementi, M. In vitro phenotypes to elvitegravir and dolutegravir in primary macrophages and lymphocytes of clonal
recombinant viral variants selected in patients failing raltegravir. J. Antimicrob. Chemother.: 2013; 68(11): 25252532 - Article
IF 2012: 5,338
P.200. Canducci, F; Debiaggi, M; Ceresola, ER; Sampaolo,
M; Alessandrino, EP; Brerra, R; Piazza, A; Clementi, M.
Infection and coinfection of human rhinovirus C in stem cell
transplant recipients. Clin. Dev. Immunol.: 2013; 2012:
236081 - Article
IF 2012: 3,064
P.201. Canessa, N; Crespi, C; Motterlini, M; Baud-Bovy,
G; Chierchia, G; Pantaleo, G; Tettamanti, M; Cappa,
SF. The functional and structural neural basis of individual
differences in loss aversion. J. Neurosci.: 2013; 33(36):
14307-14317 - Article
IF 2012: 6,908
P.202. Cannistraci, CV and Ogorevc, J; Zorc, M; Ravasi, T;
Dovc, P; Kunej, T. Pivotal role of the muscle-contraction
pathway in cryptorchidism and evidence for genomic connections with cardiomyopathy pathways in RASopathies.
BMC Med. Genomics: 2013; 6: 5 - Article
IF 2012: 3,466
P.203. Cantarelli, E; Citro, A; Marzorati, S; Melzi, R; Scavini, M; Piemonti, L. Murine animal models for preclinical
islet transplantation: No model fits all (research purposes).
Islets: 2013; 5(2): 79-86 - Review
IF 2012: 1,545
P.204. Cantiello, F; Cicione, A; Salonia, A; Autorino, R; Tucci,
L; Madeo, I; Damiano, R. Periurethral fibrosis secondary to
prostatic inflammation causing lower urinary tract symptoms: A prospective cohort study. Urology: 2013; 81(5):
1018-1023 - Article
IF 2012: 2,424
P.205. Canto, MI; Harinck, F; Hruban, RH; Offerhaus, GJ; Poley, JW; Kamel, I; Nio, Y; Schulick, RS; Bassi, C; Kluijt, I;
Levy, MJ; Chak, A; Fockens, P; Goggins, M; Bruno, M; on
behalf of the International Cancer of the Pancreas
Screening (CAPS) Consortium. International Cancer of
the Pancreas Screening (CAPS) Consortium summit on
the management of patients with increased risk for familial
pancreatic cancer. Gut: 2013; 62(3): 339-347 - Article
IF 2012: 10,732
P.206. Canu, E; Agosta, F; Galantucci, S; Chiò, A; Riva, N;
Silani, V; Falini, A; Comi, G; Filippi, M. Extramotor damage is associated with cognition in primary lateral sclerosis
patients. PLoS One: 2013; 8(12): e82017 - Article
IF 2012: 3,730
P.207. Canu, E and Agosta, F; Spinelli, EG; Magnani, G;
Marcone, A; Scola, E; Falautano, M; Comi, G; Falini, A;
Filippi, M. White matter microstructural damage in
Alzheimer’s disease at different ages of onset. Neurobiol.
Aging: 2013; 34(10): 2331-2340 - Article
IF 2012: 6,166
P.208. Capitanio, JF; Mazza, E; Motta, M; Mortini, P; Reni,
M. Mechanisms, indications and results of salvage systemic therapy for sporadic and von Hippel-Lindau related
hemangioblastomas of the central nervous system. Crit.
Rev. Oncol. Hematol.: 2013; 86(1): 69-84 - Review
IF 2012: 4,637
P.209. Capitanio, U; Abdollah, F; Matloob, R; Salonia, A;
Suardi, N; Briganti, A; Carenzi, C; Rigatti, P; Montorsi,
F; Bertini, R. Effect of number and location of distant
PUBLICATIONS
metastases on renal cell carcinoma mortality in candidates
for cytoreductive nephrectomy: Implications for multimodal
therapy. Int. J. Urol.: 2013; 20(6): 572-579 - Article
IF 2012: 1,734
P.210. Capitanio, U; Abdollah, F; Matloob, R; Suardi, N;
Castiglione, F; Di Trapani, E; Capogrosso, P; Gallina,
A; Dell’Oglio, P; Briganti, A; Salonia, A; Montorsi, F;
Bertini, R. When to perform lymph node dissection in patients with renal cell carcinoma: a novel approach to the
preoperative assessment of risk of lymph node invasion at
surgery and of lymph node progression during follow-up.
BJU Int: 2013; 112(2): E59-E66 - Article
IF 2012: 3,046
P.211. Capitanio, U; Briganti, A. Editorial Comment to Nodal
involvement at nephrectomy is associated with worse survival: A stage-for-stage and grade-for-grade analysis. Int. J.
Urol.: 2013; 20(4): 380-381 - Comment
P.212. Capitanio, U; Salonia, A; Briganti, A; Montorsi, F.
Silodosin in the management of lower urinary tract symptoms as a result of benign prostatic hyperplasia: Who are
the best candidates. Int. J. Clin. Pract.: 2013; 67(6): 544551 - Review
IF 2012: 2,427
P.213. Capitanio, U; Suardi, N; Matloob, R; Abdollah, F;
Castiglione, F; Briganti, A; Carenzi, C; Roscigno, M;
Montorsi, F; Bertini, R. Staging lymphadenectomy in renal cell carcinoma must be extended: a sensitivity curve
analysis. BJU Int.: 2013; 111(3): 412-418 - Article
IF 2012: 3,046
P.214. Capobianco, A; Rovere-Querini, P. Endometriosis, a
disease of the macrophage. Front. Immunol.: 2013; 4: 9 Review
IF 2012: No Impact Factor
P.215. Capogrosso, P; Colicchia, M; Ventimiglia, E;
Castagna, G; Clementi, MC; Suardi, N; Castiglione, F;
Briganti, A; Cantiello, F; Damiano, R; Montorsi, F; Salonia, A. One patient out of four with newly diagnosed erectile dysfunction is a young man—worrisome picture from
the everyday clinical practice. J. Sex. Med.: 2013; 10(7):
1833-1841 - Article
IF 2012: 3,513
P.216. Cappellari, M; Bovi, P; Moretto, G; Zini, A; Nencini, P;
Sessa, M; Furlan, M; Pezzini, A; Orlandi, G; Paciaroni, M;
Tassinari, T; Procaccianti, G; Di Lazzaro, V; Bettoni, L;
Gandolfo, C; Silvestrelli, G; Rasura, M; Martini, G; Melis,
M; Calloni, MV; Chiodo-Grandi, F; Beretta, S; Guarino, M;
Altavista, MC; Marcheselli, S; Galletti, G; Adobbati, L; Del
Sette, M; Mancini, A; Orrico, D; Monaco, S; Cavallini, A;
Sciolla, R; Federico, F; Scoditti, U; Brusaferri, F; Grassa,
C; Specchio, L; Bongioanni, MR; Sparaco, M; Zampolini,
M; Greco, G; Colombo, R; Passarella, B; Adami, A; Consoli, D; Toni, D. The THRombolysis and STatins (THRaST)
study. Neurology: 2013; 80(7): 655-661 - Article
IF 2012: 8,249
P.217. Cappellari, O; Benedetti, S; Innocenzi, A; Tedesco,
FS; Moreno-Fortuny, A; Ugarte, G; Lampugnani, MG;
Messina, G; Cossu, G. Dll4 and PDGF-BB Convert Committed Skeletal Myoblasts to Pericytes without Erasing
Their Myogenic Memory. Dev. Cell: 2013; 24(6): 586-599
- Article
IF 2012: 12,861
P.218. Capua, I; Mercalli, A; Pizzuto, MS; Romero-Tejeda, A;
Kasloff, S; De Battisti, C; Bonfante, F; Patrono, LV; Vicenzi, E; Zappulli, V; Lampasona, V; Stefani, A; Doglioni, C;
Terregino, C; Cattoli, G; Piemonti, L. Influenza A viruses
grow in human pancreatic cells and cause pancreatitis and
diabetes in an animal model. J. Virol.: 2013; 87(1): 597610 - Article
IF 2012: 5,076
P.219. Capurso, G; Boccia, S; Salvia, R; Del Chiaro, M; Frulloni, L; Arcidiacono, PG; Zerbi, A; Manta, R; Fabbri, C;
Ventrucci, M; Tarantino, I; Piciucchi, M; Carnuccio, A; Bog-
gi, U; Leoncini, E; Costamagna, G; Delle Fave, G; Pezzilli,
R; Bassi, C; Larghi, A; for the Italian Association for the
Study of the Pancreas (AISP), Intraductal Papillary Mucinous Neoplasm (IPMN) Study Group. Risk factors for intraductal papillary mucinous neoplasm (ipmn) of the pancreas: A multicentre case-control study. Am. J. Gastroenterol.: 2013; 108(6): 1003-1009 - Article
IF 2012: 7,553
P.220. Carbone, A; Bigoloni, A; Galli, L; Spagnuolo, V; Gianotti, N; Lazzarin, A; Castagna, A. Glucose tolerance in
HIV-1 treated patients who switched from boosted-protease inhibitors to etravirine. AIDS: 2013; 27(16): 26612663 - Letter
IF 2012: 6,407
P.221. Carbone, A; Spina, M; Gloghini, A; Ponzoni, M;
Doglioni, C; Tirelli, U. Nodular lymphocyte predominant
Hodgkin lymphoma with non-invasive or early invasive
growth pattern suggests an early step of the disease with a
highly favorable outcome. Am. J. Hematol.: 2013; 88(2):
161-162 - Letter
IF 2012: 4,138
P.222. Carlotta, D; Borroni, S; Maffei, C; Fossati, A. On the
relationship between retrospective childhood ADHD symptoms and adult BPD features: The mediating role of actionoriented personality traits. Compr. Psychiatry: 2013; 54(7):
943-952 - Article
IF 2012: 2,376
P.223. Carobene, A; Braga, F; Roraas, T; Sandberg, S;
Bartlett, WA. A systematic review of data on biological variation for alanine aminotransferase, aspartate aminotransferase and ?-glutamyl transferase. Clin. Chem. Lab. Med.:
2013; 51(10): 1997-2007 - Article
IF 2012: 3,009
P.224. Carobene, A; Guerra, E; Ceriotti, F. A mechanismbased way to evaluate commutability of control materials
for enzymatic measurements. The example of gamma-glutamyltransferase. Clin. Chim. Acta: 2013; 424: 153-158 Article
IF 2012: 2,850
P.225. Carotenuto, M; Pedone, E and Diana, D and De Antonellis, P; Dzeroski, S; Marino, N; Navas, L; Di Dato, V;
Scoppettuolo, MN; Cimmino, F; Correale, S; Pirone, L;
Monti, SM; Bruder, E; Zenko, B; Slavkov, I; Pastorino, F;
Ponzoni, M; Schulte, JH; Schramm, A; Eggert, A; Westermann, F; Arrigoni, G; Accordi, B; Basso, G; Saviano, M;
Fattorusso, R; Zollo, M. Neuroblastoma tumorigenesis is
regulated through the Nm23-H1/h-Prune C-terminal interaction. Sci. Rep.: 2013; 3: Article number: 1351: - Article
IF 2012: 2,927
P.226. Carraro, F and Cicalese, MP; Cesaro, S; De Santis, R;
Zanazzo, G; Tornesello, A; Giordano, P; Bergadano, A;
Giacchino, M. Guidelines for the use of long-term central
venous catheter in children with hemato-oncological disorders. On behalf of supportive therapy working group of Italian Association of Pediatric Hematology and Oncology
(AIEOP). Ann. Hematol.: 2013; 92(10): 1405-1412 - Article
IF 2012: 2,866
P.227. Carvalho, ACC; Schumacher, RF; Bigoni, S; Soncini, E;
Notarangelo, L; Apostoli, A; Bonfanti, C; Cirillo, D; Mantegani, P; Porta, F; Comelli, M; Matteelli, A. Contact investigation based on serial interferon-gamma release assays
(IGRA) in children from the hematology-oncology ward after exposure to a patient with pulmonary tuberculosis. Infection: 2013; 41(4): 827-831 - Article
IF 2012: 2,440
P.228. Casalini, F and Fugazza, L; Esposito, G; Cabella, C;
Brioschi, C; Cordaro, A; D’Angeli, L; Bartoli, A; Filannino,
AM; Gringeri, CV; Longo, DL; Muzio, V; Nuti, E; Orlandini,
E; Figlia, G; Quattrini, A; Tei, L; Digilio, G; Rossello, A;
Maiocchi, A. Synthesis and Preliminary Evaluation in Tumor
Bearing Mice of New 18F-Labeled Arylsulfone Matrix Metal-
337
PUBLICATIONS
loproteinase Inhibitors as Tracers for Positron Emission Tomography. J. Med. Chem.: 2013; 56(6): 2676-2689 - Article
IF 2012: 5,614
P.229. Casarotto, S; Canali, P; Rosanova, M; Pigorini, A; Fecchio, M; Mariotti, M; Lucca, A; Colombo, C; Benedetti,
F; Massimini, M. Assessing the Effects of Electroconvulsive Therapy on Cortical Excitability by Means of Transcranial Magnetic Stimulation and Electroencephalography.
Brain Topogr.: 2013; 26(2): 326-337 - Article
IF 2012: 3,671
P.230. Cascavilla, ML; Querques, G; Querques, L; Codenotti, M; Bandello, F. Intravitreal Ranibizumab for myopic
choroidal neovascularization after pars plana vitrectomy
and silicone oil tamponade. Eur. J. Ophthalmol.: 2013;
23(6): 913-916 - Article
IF 2012: 0,912
P.231. Casiraghi, F; Lertwattanarak, R and Luzi, L; Chavez,
AO; Davalli, AM; Naegelin, T; Comuzzie, AG; Frost, P;
Musi, N; Folli, F. Energy Expenditure Evaluation in Humans
and Non-Human Primates by SenseWear Armband. Validation of Energy Expenditure Evaluation by SenseWear
Armband by Direct Comparison with Indirect Calorimetry.
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the Study of Metabolic Diseases and Neonatal Screening,
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P.244. Castellucci, P; Picchio, M. 11C-Choline PET/CT and
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getto Informatizzato Pancreatite Acuta, Associazione
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P.254. Cattaneo, A; Sitia, R. Remembering Michael S. Neuberger (1953-2013). EMBO J.: 2013; 32(24): 3112-3113
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P.257. Cavalli, G; D’Aliberti, T. Charcot’s arthropathy of the
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P.279. Ciceri, F; Lupo-Stanghellini, MT; Korthof, ET; on behalf of the SAA-WP EBMT. Haploidentical transplantation in
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P.281. Cifola, I; Pietrelli, A; Consolandi, C; Severgnini, M;
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P.286. Claessen, BE; Dangas, GD; Godino, C; Henriques,
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P.288. Clifford, DB; Nath, A; Cinque, P; Brew, BJ; Zivadinov,
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P.295. Cohen, JA; Barkhof, F; Comi, G; Izquierdo, G; Khatri,
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P.299. Colombo, B; Dalla Libera, D; Volonté, MA; Spagnolo, F; Dalla Costa, G; Martinelli, V; Comi, G. Migralepsy:
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P.300. Colombo, E; Bedogni, F; Lorenzetti, I; Landsberger,
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P.305. Comi, G. Disease-modifying treatments for progressive
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IF 2012: 1,412
P.307. Comi, G; Battaglia, MA; Bertolotto, A; Sette, MD;
Ghezzi, A; Malferrari, G; Salvetti, M; Sormani, MP; Tesio, L;
Stolz, E; Zaratin, P; Mancardi, G. Observational case-control study of the prevalence of chronic cerebrospinal venous insufficiency in multiple sclerosis: Results from the
CoSMo study. Mult. Scler.: 2013; 19(11): 1508-1517 - Article
IF 2012: 4,472
P.308. Comi, G; Cook, SD; Giovannoni, G; Rammohan, K;
Rieckmann, P; Sorensen, PS; Vermersch, P; Hamlett, AC;
Viglietta, V; Greenberg, SJ. MRI outcomes with cladribine
tablets for multiple sclerosis in the CLARITY study. J. Neurol.: 2013; 260(4): 1136-1146 - Article
IF 2012: 3,578
P.309. Comi, G; Hartung, HP; Kurukulasuriya, NC; Greenberg, SJ; Scaramozza, M. Cladribine tablets for the treatment of relapsing-remitting multiple sclerosis. Expert Opin.
Pharmacother.: 2013; 14(1): 123-136 - Review
IF 2012: 2,860
P.310. Comi, G; Martinelli, V; Rodegher, M; Moiola, L; Leocani, L; Bajenaru, O; Carra, A; Elovaara, I; Fazekas, F;
Hartung, HP; Hillert, J; King, J; Komoly, S; Lubetzki, C;
Montalban, X; Myhr, KM; Preziosa, P; Ravnborg, M;
Rieckmann, P; Rocca, MA; Wynn, D; Young, C; Filippi,
M. Effects of early treatment with glatiramer acetate in patients with clinically isolated syndrome. Mult. Scler.: 2013;
19(8): 1074-1078 - Article
IF 2012: 4,472
P.311. Condliffe, SB; Fratangeli, A; Munasinghe, NR; Saba, E;
Passafaro, M; Montrasio, C; Ferrari, M; Rosa, P; Carrera, P. The E1015K variant in the synprint region of the
CaV2.1 channel alters channel function and is associated
with different migraine phenotypes. J. Biol. Chem.: 2013;
288(47): 33873-33883 - Article
IF 2012: 4,651
P.312. Consalez, GG; Hawkes, R. The compartmental restriction of cerebellar interneurons. Front. Neural Circuits:
2013; 6: 123 - Review
IF 2012: 3,333
P.313. Consonni, M; Cafiero, R; Marin, D; Tettamanti, M;
Iadanza, A; Fabbro, F; Perani, D. Neural convergence for
language comprehension and grammatical class production in highly proficient bilinguals is independent of age of
acquisition. Cortex: 2013; 49(5): 1252-1258 - Article
IF 2012: 6,161
P.314. Consonni, M; Iannaccone, S; Cerami, C; Frasson,
P; Lacerenza, M; Lunetta, C; Corbo, M; Cappa, SF. The
cognitive and behavioural profile of Amyotrophic Lateral
Sclerosis: Application of the consensus criteria. Behav.
Neurol.: 2013; 27(2): 143-153 - Article
IF 2012: 1,247
P.315. Copie-Bergman, C; Wotherspoon, AC; Capella, C;
Motta, T; Pedrinis, E; Pileri, SA; Bertoni, F; Conconi, A;
Zucca, E; Ponzoni, M and Ferreri, AJ. Gela histological
scoring system for post-treatment biopsies of patients with
gastric MALT lymphoma is feasible and reliable in routine
practice. Br. J. Haematol.: 2013; 160(1): 47-52 - Article
IF 2012: 4,942
P.316. Corada, M and Orsenigo, F; Morini, MF; Pitulescu, ME;
Bhat, G; Nyqvist, D; Breviario, F; Conti, V; Briot, A; IruelaArispe, ML; Adams, RH; Dejana, E. Sox17 is indispensable for acquisition and maintenance of arterial identity. Nat.
Commun.: 2013; 4: Article number: 2609 - Article
IF 2012: 10,015
P.317. Correale, C and Genua, M and Vetrano, S; Mazzini, E;
Martinoli, C; Spinelli, A; Arena, V; Biroulet, LP; Caprioli, F;
Passini, N; Panina-Bordignon, P; Repici, A; Malesci, A;
Rutella, S; Rescigno, M; Danese, S. The Bacterial Sensor
Triggering Receptor Expressed on Myeloid Cells-2 Regulates the Mucosal Inflammatory Response. Gastroenterology: 2013; 144(2): 346-356.e3 - Article
IF 2012: 12,821
P.318. Correale, M; Ieva, R; Pappalardo, F; Santoro, F; De
Bonis, M; Di Biase, M. Gastrointestinal bleeding and coagulation disorders in a patient with left-ventricular assist
device. J. Cardiovasc. Med.: 2013; 14(2): 173-174 - Letter
IF 2012: 2,657
P.319. Cortese, K; Howes, MT; Lundmark, R; Tagliatti, E; Bagnato, P; Petrelli, A; Bono, M; McMahon, HT; Parton, RG;
341
PUBLICATIONS
Tacchetti, C. The HSP90 inhibitor geldanamycin perturbs
endosomal structure and drives recycling ErbB2 and transferrin to modified MVBs/lysosomal compartments. Mol. Biol. Cell.: 2013; 24(2): 129-144 - Article
IF 2012: 4,803
P.320. Cortese, K; Vicidomini, G; Gagliani, MC; Boccacci, P;
Diaspro, A; Tacchetti, C. High data output method for 3-D
correlative light-electron microscopy using ultrathin
cryosections. Methods Mol. Biol.: 2013; 950(): 417-437 Article
IF 2012: No Impact Factor
P.321. Corti, A; Curnis, F; Rossoni, G; Marcucci, F; Gregorc, V. Peptide-mediated targeting of cytokines to tumor
vasculature: the NGR-hTNF example. BioDrugs: 2013;
27(6): 591-603 - Review
IF 2012: 2,809
P.322. Corti, L; Papaleo, E; Pagliardini, L; Rabellotti, E;
Molgora, M; La Marca, A; Viganò, P; Candiani, M. Fresh
blastocyst transfer as a clinical approach to overcome the
detrimental effect of progesterone elevation at hCG triggering: A strategy in the context of the Italian law. Eur. J. Obstet. Gynecol. Reprod. Biol.: 2013; 171(1): 73-77 - Article
IF 2012: 1,843
P.323. Cortinovis, D; Beretta, G; Piazza, E; Luchena, G; Aglione, S; Bertolini, A; Buzzoni, R; Cabiddu, M; Carnaghi, C;
Danova, M; Farina, G; Ferrari, V; Frascaroli, M; Reni, M;
Tansini, G; on behalf of AIOM Lombardia. Chemotherapyinduced anemia and oncologist perception on treatment:
results of a web-based survey. Tumori: 2013; 99(1): 45-50
- Review
IF 2012: 0,922
P.324. Coscas, G; Augustin, A; Bandello, F; de Smet, MD;
Lanzetta, P; Staurenghi, G; Parravano, MC; Udaondo, P;
Moisseiev, E; Soubrane, G; Yatziv, Y; Loewenstein, A. Retreatment with Ozurdex for macular edema secondary to
retinal vein occlusion. Eur. J. Ophthalmol.: 2013; 24(1): 19 - Article
IF 2012: 0,912
P.325. Coscas, G; Coscas, F; Zucchiatti, I; Bandello, F;
Soubrane, G; Souied, E. SD-OCT stages of progression of
type 2 macular telangiectasia in a patient followed for 3
years. Eur. J. Ophthalmol.: 2013; 23(6): 917-921 - Article
IF 2012: 0,912
P.326. Cossarini, F; Spagnuolo, V; Gianotti, N; Carbone, A;
Lazzarin, A; Castagna, A. Management of HIV infection
after triple class failure. New Microbiol.: 2013; 36(1): 2339 - Review
IF 2012: 1,667
P.327. Costopoulos, C; Latib, A; Naganuma, T; Sticchi, A;
Chieffo, A; Figini, F; Carlino, M; Montorfano, M; Naim,
C; Kawaguchi, M; Giannini, F; Colombo, A. Comparison of first- and second-generation drug-eluting stents in
saphenous vein grafts used as aorto-coronary conduits.
Am. J. Cardiol.: 2013; 112(3): 318-322 - Article
IF 2012: 3,209
P.328. Costopoulos, C; Latib, A; Naganuma, T; Sticchi, A;
Figini, F; Basavarajaiah, S; Carlino, M; Chieffo, A;
Montorfano, M; Naim, C; Kawaguchi, M; Giannini, F;
Colombo, A. The role of drug-eluting balloons alone or in
combination with drug-eluting stents in the treatment of de
novo diffuse coronary disease. JACC Cardiovasc. Interventions: 2013; 6(11): 1153-1159 - Article
IF 2012: 6,552
P.329. Costopoulos, C; Latib, A; Naganuma, T; Sticchi, A;
Giannini, F; Colombo, A. Newly available and recent advances in drug-eluting stents. Exp. Rev. Cardiovasc. Ther.:
2013; 11(5): 555-566 - Review
IF 2012: No Impact Factor
P.330. Costopoulos, C; Naganuma, T; Latib, A; Colombo,
A. Optical coherence tomography of a bifurcation lesion
treated with bioresorbable vascular scaffolds with the “mi-
ni-crush” technique. JACC Cardiovasc. Interv.: 2013;
6(12): 1326-1327 - Images
P.331. Costopoulos, C; Naganuma, T; Latib, A; Colombo,
A. Looking into the future with bioresorbable vascular scaffolds. Expert Rev. Cardiovasc. Ther.: 2013; 11(10): 14071416 - Review
IF 2012: No Impact Factor
P.332. Cousminer, DL; Berry, DJ; Timpson, NJ; Ang, W; Thiering, E; Byrne, EM; Taal, HR; Huikari, V; Bradfield, JP; Kerkhof, M; Groen-Blokhuis, MM; Kreiner-Møller, E; Marinelli,
M; Holst, C; Leinonen, JT; Perry, JR; Surakka, I; Pietiläinen,
O; Kettunen, J; Anttila, V; Kaakinen, M; Sovio, U; Pouta, A;
Das, S; Lagou, V; Power, C; Prokopenko, I; Evans, DM;
Kemp, JP; St Pourcain, B; Ring, S; Palotie, A; Kajantie, E;
Osmond, C; Lehtimäki, T; Viikari, JS; Kähönen, M; Warrington, NM; Lye, SJ; Palmer, LJ; Tiesler, CM; Flexeder, C;
Montgomery, GW; Medland, SE; Hofman, A; Hakonarson,
H; Guxens, M; Bartels, M; Salomaa, V; ReproGen Consortium; Murabito, JM; Kaprio, J; Sørensen, TI; Ballester,
F; Bisgaard, H; Boomsma, DI; Koppelman, GH; Grant, SF;
Jaddoe, VW; Martin, NG; Heinrich, J; Pennell, CE;
Raitakari, OT; Eriksson, JG; Smith, GD; Hyppönen, E;
Järvelin, MR; McCarthy, MI; Ripatti, S; Widén, E; for the
Early Growth Genetics (EGG) Consortium. Genome-wide
association and longitudinal analyses reveal genetic loci
linking pubertal height growth, pubertal timing and childhood adiposity. Hum. Mol. Genet.: 2013; 22(13): 27352747 - Article
IF 2012: 7,692
P.333. Cozzi, A; Santambrogio, P; Privitera, D; Broccoli, V;
Rotundo, LI; Garavaglia, B; Benz, R; Altamura, S; Goede,
JS; Muckenthaler, MU and Levi, S. Human L-ferritin deficiency is characterized by idiopathic generalized seizures
and atypical restless leg syndrome. J. Exp. Med.: 2013;
210(9): 1779-1791 - Article
IF 2012: 13,214
P.334. Crespi, R; Capparè, P; Gherlone, E. Electrical mallet
provides essential advantages in maxillary bone condensing. A prospective clinical study. Clin. Implant Dent. Relat.
Res.: 2013; 15(6): 874-882 - Article
IF 2012: 3,821
P.335. Crespi, R; Capparè, P; Gherlone, EF. Electrical mallet
in implants placed in fresh extraction sockets with simultaneous osteotome sinus floor elevation. Int. J. Oral Maxillofac. Implants: 2013; 28(3): 869-874 - Article
IF 2012: 1,908
P.336. Crippa, L; Bianco, M; Colombo, B; Gasparri, AM;
Ferrero, E; Loh, YP; Curnis, F; Corti, A. A new chromogranin A-dependent angiogenic switch activated by thrombin. Blood: 2013; 121(2): 392-402 - Article
IF 2012: 9,060
P.337. Crivello, P and Lauterbach, N; Zito, L; Sizzano, F;
Toffalori, C; Marcon, J; Curci, L; Mulder, A; Wieten, L;
Zino, E; Voorter, CEM; Tilanus, MGJ; Fleischhauer, K. Effects of transmembrane region variability on cell surface
expression and allorecognition of HLA-DP3. Hum. Immunol.: 2013; 74(8): 970-977 - Article
IF 2012: 2,298
P.338. Crutch, SJ; Schott, JM; Rabinovici, GD; Boeve, BF;
Cappa, SF; Dickerson, BC; Dubois, B; Graff-Radford, NR;
Krolak-Salmon, P; Lehmann, M; Mendez, MF; Pijnenburg,
Y; Ryan, NS; Scheltens, P; Shakespeare, T; Tang-Wai, DF;
Van Der Flier, WM; Bain, L; Carrillo, MC; Fox, NC. Shining
a light on posterior cortical atrophy. Alzheimers. Dement.:
2013; 9(4): 463-465 - Editorial
P.339. Curnis, F; Sacchi, A; Longhi, R; Colombo, B; Gasparri, A; Corti, A. IsoDGR-Tagged Albumin: A New
αvβ33 Selective Carrier for Nanodrug Delivery to Tumors.
Small: 2013; 9(5): 673-678 - Article
IF 2012: 7,823
P.340. Dacci, P; Amadio, S; Gerevini, S; Moiola, L; Del
Carro, U; Radaelli, M; Figlia, G; Martinelli, V; Comi, G;
PUBLICATIONS
Fazio, R. Practice of yoga may cause damage of both sciatic nerves: a case report. Neurol. Sci.: 2013; 34(3): 393396 - Article
IF 2012: 1,412
P.341. D’Addio, F and Boenisch, O and Magee, CN; Yeung,
MY; Yuan, X; Mfarrej, B; Vergani, A; Ansari, MJ; Fiorina,
P; Najafian, N. Prolonged, Low-Dose Anti-Thymocyte
Globulin, Combined with CTLA4-Ig, Promotes Engraftment
in a Stringent Transplant Model. PLoS ONE: 2013; 8(1):
e53797 - Article
IF 2012: 3,730
P.342. D’Addio, F; Ueno, T; Clarkson, M; Zhu, B; Vergani, A;
Freeman, GJ; Sayegh, MH; Ansari, MJI; Fiorina, P;
Habicht, A. CD160Ig Fusion Protein Targets a Novel Costimulatory Pathway and Prolongs Allograft Survival. PLoS
ONE: 2013; 8(4): e60391 - Article
IF 2012: 3,730
P.343. Dagna, L; Pritchett, JC; Lusso, P. Immunomodulation
and immunosuppression by human herpesvirus 6A and
6B. Future Virol.: 2013; 8(3): 273-287 - Review
IF 2012: 0,962
P.344. Dakanalis, A; Zanetti, MA; Riva, G; Clerici, M. Psychosocial moderators of the relationship between body
dissatisfaction and symptoms of eating disorders: A look at
a sample of young Italian women. Revue Europeene de
Psychologie Appliquee: 2013; 63(5): 323-334 - Article
IF 2012: 0,489
P.345. D’Alessandro, R; Meldolesi, J. Expression and function
of the dense-core vesicle membranes are governed by the
transcription repressor REST. FEBS Lett.: 2013; 587(13):
1915-1922 - Review
IF 2012: 3,582
P.346. Dalla Costa, G; Colombo, B; Dalla Libera, D; Martinelli, V; Comi, G. Parry Romberg Syndrome associated
with chronic facial pain. J. Clin. Neurosci.: 2013; 20(9):
1320-1322 - Article
IF 2012: 1,253
P.347. D’Amato, R and Tomberli, B; Castelli, G; Spoladore,
R; Girolami, F; Fornaro, A; Caldini, A; Torricelli, F; Camici,
P; Gensini, GF; Cecchi, F; Olivotto, I. Prognostic value of
N-terminal pro-brain natriuretic peptide in outpatients with
hypertrophic cardiomyopathy. Am. J. Cardiol.: 2013;
112(8): 1190-1196 - Article
IF 2012: 3,209
P.348. D’Ambrosio, D; Zagni, F; Spinelli, AE; Marengo, M. Attenuation correction for small animal PET images: A comparison of two methods. Comp. Math. Methods Med.:
2013; 2013: 103476 - Article
IF 2012: 0,791
P.349. D’Andrea, A; Mele, D; Nistri, S; Riegler, L; Galderisi, M;
Agricola, E; Losi, MA; Ballo, P; Mondillo, S; Badano, LP;
On behalf of the Working Group Nucleus on Echocardiography of the Italian Society of Cardiology. The prognostic
impact of dynamic ventricular dyssynchrony in patients
with idiopathic dilated cardiomyopathy and narrow QRS.
Eur. Heart J. Cardiovasc. Imaging: 2013; 14(2): 183-189 Article
IF 2012: Indexed by JCR 2012
P.350. D’Antonio, M; Musner, N; Scapin, C; Ungaro, D; Del
Carro, U; Ron, D; Feltri, ML; Wrabetz, L. Resetting translational homeostasis restores myelination in charcot-marietooth disease type 1B mice. J. Exp. Med.: 2013; 210(4):
821-838 - Article
IF 2012: 13,214
P.351. Dauvilliers, Y; Postuma, RB; Ferini-Strambi, L; Arnulf, I;
Hogl, B; Manni, R; Miyamoto, T; Oertel, W; Fantini, ML;
Puligheddu, M; Jennum, P; Sonka, K; Zucconi, M; LeuSemenescu, S; Frauscher, B; Terzaghi, M; Miyamoto, M;
Unger, M; Desautels, A; Wolfson, C; Pelletier, A; Montplaisir, J. Family history of idiopathic REM behavior disorder
a multicenter case-control study. Neurology: 2013; 80(24):
2233-2235 - Article
IF 2012: 8,249
P.352. Davis, LK; Yu, D; Keenan, CL; Gamazon, ER; Konkashbaev, AI; Derks, EM; Neale, BM; Yang, J; Lee, SH; Evans,
P; Barr, CL; Bellodi, L; Benarroch, F; Berrio, GB; Bienvenu, OJ; Bloch, MH; Blom, RM; Bruun, RD; Budman, CL;
Camarena, B; Campbell, D; Cappi, C; Cardona Silgado,
JC; Cath, DC; Cavallini, MC; Chavira, DA; Chouinard, S;
Conti, DV; Cook, EH; Coric, V; Cullen, BA; Deforce, D; Delorme, R; Dion, Y; Edlund, CK; Egberts, K; Falkai, P; Fernandez, TV; Gallagher, PJ; Garrido, H; Geller, D; Girard,
SL; Grabe, HJ; Grados, MA; Greenberg, BD; Gross-Tsur,
V; Haddad, S; Heiman, GA; Hemmings, SMJ; Hounie, AG;
Illmann, C; Jankovic, J; Jenike, MA; Kennedy, JL; King,
RA; Kremeyer, B; Kurlan, R; Lanzagorta, N; Leboyer, M;
Leckman, JF; Lennertz, L; Liu, C; Lochner, C; Lowe, TL;
Macciardi, F; McCracken, JT; McGrath, LM; Mesa Restrepo, SC; Moessner, R; Morgan, J; Muller, H; Murphy, DL;
Naarden, AL; Ochoa, WC; Ophoff, RA; Osiecki, L; Pakstis,
AJ; Pato, MT; Pato, CN; Piacentini, J; Pittenger, C; Pollak,
Y; Rauch, SL; Renner, TJ; Reus, VI; Richter, MA; Riddle,
MA; Robertson, MM; Romero, R; Rosario, MC; Rosenberg, D; Rouleau, GA; Ruhrmann, S; Ruiz-Linares, A;
Sampaio, AS; Samuels, J; Sandor, P; Sheppard, B;
Singer, HS; Smit, JH; Stein, DJ; Strengman, E; Tischfield,
JA; Valencia Duarte, AV; Vallada, H; Van Nieuwerburgh, F;
Veenstra-VanderWeele, J; Walitza, S; Wang, Y; Wendland,
JR; Westenberg, HGM; Shugart, YY; Miguel, EC; McMahon, W; Wagner, M; Nicolini, H; Posthuma, D; Hanna, GL;
Heutink, P; Denys, D; Arnold, PD; Oostra, BA; Nestadt, G;
Freimer, NB; Pauls, DL; Wray, NR; Stewart, SE and Mathews, CA and Knowles, JA and Cox, NJ and Scharf, JM.
Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture. PLoS Genet.: 2013; 9(10): e1003864 Article
IF 2012: 8,517
P.353. De Benedetto, U; Battaglia Parodi, M; Knutsson,
KA; Lattanzio, R; Bandello, F; Iacono, P. Macular hole after injection of dexamethasone intravitreal implant for macular oedema due to central retinal vein occlusion. Acta
Ophthalmol.: 2013; 91(1): e75-e77 - Letter
IF 2012: 2,345
P.354. De Bonis, M; Bolling, SF. Mitral valve surgery: wait and
see vs. early operation. Eur. Heart J.: 2013; 34(1): 13-19 Review
IF 2012: 14,097
P.355. De Bonis, M; Lapenna, E; Alfieri, O. Edge-to-edge
Alfieri technique for mitral valve repair: which indications?.
Curr Opin Cardiol: 2013; 28(2): 152-157 - Review
IF 2012: 2,564
P.356. De Bonis, M; Lapenna, E; Buzzatti, N; Taramasso,
M; Calabrese, MC; Nisi, T; Pappalardo, F; Alfieri, O.
Can the edge-to-edge technique provide durable results
when used to rescue patients with suboptimal conventional mitral repair?. Eur. J. Cardio-thorac. Surg.: 2013; 43(6):
e173-e179 - Article
IF 2012: 2,674
P.357. De Bonis, M; Lapenna, E; Giacomini, A; Alfieri, O.
Secondary mitral regurgitation in patients undergoing aortic
valve replacement. Eur. J. Cardiothorac. Surg.: 2013;
44(1): 40-41 - Comment
P.358. de Candia, P; Torri, A; Gorletta, T; Fedeli, M; Bulgheroni, E; Cheroni, C; Marabita, F; Crosti, M; Moro, M; Pariani,
E; Romano, L; Esposito, S; Mosca, F; Rossetti, G; Rossi,
RL; Geginat, J; Casorati, G; Dellabona, P; Pagani, M;
Abrignani, S. Intracellular Modulation, Extracellular Disposal
and Serum Increase of MiR-150 Mark Lymphocyte Activation. PLoS ONE: 2013; 8(9): e75348 - Article
IF 2012: 3,730
343
PUBLICATIONS
P.359. De Carlo, M; Giannini, C; Fiorina, C; Bedogni, F; Napodano, M; Klugmann, S; Tamburino, C; Maisano, F; Santoro, G; Ettori, F; Petronio, AS. Paravalvular leak after
CoreValve implantation in the Italian Registry: predictors
and impact on clinical outcome. Int J Cardiol: 2013;
168(5): 5088-5089 - Letter
IF 2012: 5,509
P.360. De Cobelli, F; Giganti, F; Orsenigo, E; Cellina, M; Esposito, A; Agostini, G; Albarello, L; Mazza, E; Ambrosi,
A; Socci, C; Staudacher, C; Del Maschio, A. Apparent
diffusion coefficient modifications in assessing gastro-oesophageal cancer response to neoadjuvant treatment:
comparison with tumour regression grade at histology. Eur.
Radiol.: 2013; 23(8): 2165-2174 - Article
IF 2012: 3,548
P.361. De Falco, L and Sanchez, M; Silvestri, L; Kannengiesser, C; Muckenthaler, MU; Iolascon, A; Gouya, L;
Camaschella, C; Beaumont, C. Iron refractory iron deficiency anemia. Haematologica: 2013; 98(6): 845-853 Review
IF 2012: 5,935
P.362. De Feo, D; Colombo, B; Dalla Libera, D; Martinelli,
V; Comi, G. Subarachnoid neurocysticercosis with spinal
involvement presented with headache. Neurol. Sci.: 2013;
34(8): 1467-1469 - Letter
IF 2012: 1,412
P.363. De Graaff, AA; D’Hooghe, TM; Dunselman, GA; Dirksen, CD; Hummelshoj, L; WERF EndoCost Consortium;
Simoens, S. The significant effect of endometriosis on
physical, mental and social wellbeing: results from an international cross-sectional survey. Hum. Reprod.: 2013;
28(10): 2677-2685 - Article
IF 2012: 4,670
P.364. De Marzi, P; Ottolina, J; Mangili, G; Rabaiotti, E;
Ferrari, D; Viganò, R; Candiani, M. Surgical treatment of
elderly patients with endometrial cancer (=65years). J.
Geriatr. Oncol.: 2013; 4(4): 368-373 - Article
IF 2012: 1,118
P.365. De Nardi, P and Carvello, M. How reliable is current
imaging in restaging rectal cancer after neoadjuvant therapy?. World J. Gastroenterol.: 2013; 19(36): 5964-5972 Review
IF 2012: 2,547
P.366. De Nardi, P; Vignali, A. The American Society of
Colon and Rectal Surgeons 2013 annual meeting. Tech.
Coloproctol.: 2013; 17(4): 465-466 - Conference Paper
P.367. Dei Cas, A; Spigoni, V; Franzini, L; Preti, M; Ardigo, D;
Derlindati, E; Metra, M; Monti, LD; Dell’Era, P; Gnudi, L;
Zavaroni, I. Lower endothelial progenitor cell number, family history of cardiovascular disease and reduced HDL-cholesterol levels are associated with shorter leukocyte telomere length in healthy young adults. Nutr. Metab. Cardiovasc. Dis.: 2013; 23(3): 272-278 - Article
IF 2012: 3,978
P.368. Del Vecchio, L; Lusenti, T; Del Rosso, G; Malandra, R;
Balducci, A; Losito, A; on behalf of Group for Arterial
Hypertension of the Italian Society of Nephrology.
Prevalence of hypertension in a large cohort of Italian hemodialysis patients: results of a cross-sectional study. J.
Nephrol.: 2013; 26(4): 745-754 - Article
IF 2012: 2,015
P.369. Della Bella, P; Baratto, F; Tsiachris, D; Trevisi, N;
Vergara, P; Bisceglia, C; Petracca, F; Carbucicchio, C;
Benussi, S; Maisano, F; Alfieri, O; Pappalardo, F; Zangrillo, A; Maccabelli, G. Management of ventricular
tachycardia in the setting of a dedicated unit for the treatment of complex ventricular arrhythmias: Long-term outcome after ablation. Circulation: 2013; 127(13): 13591368 - Article
IF 2012: 15,202
P.370. Della Bella, P; Vergara, P. The Subcutaneous ICD: A
Niche Indication or the Next Contender of the Transvenous
ICD?. J. Cardiovasc. Electrophysiol.: 2013; 24(1): 83-85 Comment
P.371. Della Rocca, G; Di Marco, P; Beretta, L; De Gaudio,
AR; Ori, C; Mastronardi, R. Do we need to use sugammadex at the end of a general anesthesia to reverse the
action of neuromuscular bloking agents? Position paper on
sugammadex use. Minerva Anestesiol.: 2013; 79(6): 661666 - Note
IF 2012: 2,818
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Adherence to anti-Parkinson drug therapy in the “REASON” sample of Italian patients with Parkinson’s disease:
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IF 2012: 7,384
P.430. Fathi, F; Kyani, A; Darvizeh, F; Mehrpour, M; Tafazzoli,
M; Shahidi, G. Relationship Between Serum Level of Selenium and Metabolites Using 1HNMR-Based Metabonomics in Parkinson’s Disease. Appl. Magn. Reson.: 2013;
44(6): 721-734 - Article
IF 2012: 0,830
P.431. Fayad, HJ; Lamare, F; Le Rest, CC; Bettinardi, V;
Visvikis, D. Generation of 4-dimensional CT images based
on 4-dimensional PET-derived motion fields. J. Nucl. Med.:
2013; 54(4): 631-638 - Article
IF 2012: 5,774
P.432. Fellin, F; Azzeroni, R; Maggio, A; Lorentini, S; Cozzarini, C; Di Muzio, N; Fiorino, C; Calandrino, R;
Schwarz, M. Helical tomotherapy and intensity modulated
proton therapy in the treatment of dominant intraprostatic
lesion: A treament planning comparison. Radiother. Oncol.: 2013; 107(2): 207-212 - Article
IF 2012: 4,520
P.433. Ferini-Strambi, L. A need for new treatments in narcolepsy. Lancet Neurol: 2013; 12(11): 1039-1040 - Comment
P.434. Ferini-Strambi, L; Marelli, S; Galbiati, A; Castronovo, C. Effects of continuous positive airway pressure on
cognitition and neuroimaging data in sleep apnea. Int. J.
Psychophysiol.: 2013; 89(2): 203-212 - Review
IF 2012: 2,036
P.435. Fernandez-Rhodes, L; Demerath, EW; Cousminer, DL;
Tao, R; Dreyfus, JG; Esko, T; Smith, AV; Gudnason, V;
Harris, TB; Launer, L; McArdle, PF; Yerges-Armstrong, LM;
Elks, CE; Strachan, DP; Kutalik, Z; Vollenweider, P; Feenstra, B; Boyd, HA; Metspalu, A; Mihailov, E; Broer, L; Carola Zillikens, M; Oostra, B; Van Duijn, CM; Lunetta, KL; Perry, JRB; Murray, A; Koller, DL; Lai, D; Corre, T; Toniolo, D;
Albrecht, E; Stockl, D; Grallert, H; Gieger, C; Hayward, C;
Polasek, O; Rudan, I; Wilson, JF; He, C; Kraft, P; Hu, FB;
Hunter, DJ; Hottenga, JJ; Willemsen, G; Boomsma, DI;
Byrne, EM; Martin, NG; Montgomery, GW; Warrington,
NM; Pennell, CE; Stolk, L; Visser, JA; Hofman, A; Uitterlinden, AG; Rivadeneira, F; Lin, P; Fisher, SL; Bierut, LJ;
Crisponi, L; Porcu, E; Mangino, M; Zhai, G; Spector, TD;
Buring, JE; Rose, LM; Ridker, PM; Poole, C; Hirschhorn,
JN; Murabito, JM; Chasman, DI; Widen, E; North, KE;
Ong, KK; Franceschini, N. Association of adiposity genetic
variants with menarche timing in 92,105 women of European descent. Am. J. Epidemiol.: 2013; 178(3): 451-460
- Article
IF 2012: 4,780
P.436. Ferrandi, M; Barassi, P; Tadini-Buoninsegni, F; Bartolommei, G; Molinari, I; Tripodi, MG; Reina, C; Moncelli,
MR; Bianchi, G; Ferrari, P. Istaroxime stimulates SERCA2a
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and accelerates calcium cycling in heart failure by relieving
phospholamban inhibition. Br. J. Pharmacol.: 2013;
169(8): 1849-1861 - Article
IF 2012: 5,067
P.437. Ferrarello, S and Costopoulos, C; Latib, A; Naganuma, T; Sticchi, A; Figini, F; Basavarajaiah, S; Carlino,
M; Chieffo, A; Montorfano, M; Kawaguchi, M; Naim, C;
Giannini, F; Colombo, A. The role of everolimus-eluting
and resolute zotarolimus-eluting stents in the treatment of
coronary bifurcations. J. Invasive Cardiol.: 2013; 25(9):
436-440 - Article
IF 2012: 1,569
P.438. Ferrari, G; Bignami, F; Giacomini, C; Franchini, S;
Rama, P. Safety and efficacy of topical infliximab in a
mouse model of ocular surface scarring. Invest. Ophthalmol. Vis. Sci.: 2013; 54(3): 1680-1688 - Article
IF 2012: 3,441
P.439. Ferrari, G and Hajrasouliha, AR; Sadrai, Z; Ueno, H;
Chauhan, SK; Dana, R. Nerves and neovessels inhibit
each other in the cornea. Invest. Ophthalmol. Vis. Sci.:
2013; 54(1): 813-820 - Article
IF 2012: 3,441
P.440. Ferrari, G and Iuliano, L; Viganò, M; Rama, P. Impending corneal perforation after collagen cross-linking for
herpetic keratitis. J. Cataract Refractive Surg.: 2013;
39(4): 638-641 - Article
IF 2012: 2,527
P.441. Ferrari, G; Nalassamy, N; Downs, H; Dana, R; Oaklander, AL. Corneal innervation as a window to peripheral
neuropathies. Exp. Eye Res.: 2013; 113(): 148-150 - Article
IF 2012: 3,026
P.442. Ferrari, G; Ueno, H; Bignami, F; Rama, P; Dana, R.
Trigeminal stereotactic electrolysis induces dry eye in mice.
Acta Ophthalmol.: 2013; 91(2): e162-e163 - Letter
IF 2012: 2,345
P.443. Ferrari, G; Viganò, M. Bitot’s spot in vitamin A deficiency. New Engl. J. Med.: 2013; 368(22): e29 - Images
P.444. Ferrarini, M and Steimberg, N; Ponzoni, M; Belloni,
D; Berenzi, A; Girlanda, S; Caligaris-Cappio, F; Mazzoleni, G and Ferrero, E. Ex-Vivo Dynamic 3-D Culture of
Human Tissues in the RCCS™ Bioreactor Allows the
Study of Multiple Myeloma Biology and Response to Therapy. PLoS ONE: 2013; 8(8): e71613 - Article
IF 2012: 3,730
P.445. Ferreri, AJ; Govi, S; Pileri, SA; Savage, KJ. Anaplastic
large cell lymphoma, ALK-negative. Crit. R